468 results on '"Sei Sasaki"'
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2. Updates and Perspectives on Aquaporin-2 and Water Balance Disorders
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Yumi Noda and Sei Sasaki
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trafficking ,diabetes insipidus ,SIADH ,congestive heart failure ,hepatic cirrhosis ,solute-free water diuretics ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Ensuring the proper amount of water inside the body is essential for survival. One of the key factors in the maintenance of body water balance is water reabsorption in the collecting ducts of the kidney, a process that is regulated by aquaporin-2 (AQP2). AQP2 is a channel that is exclusively selective for water molecules and impermeable to ions or other small molecules. Impairments of AQP2 result in various water balance disorders, including nephrogenic diabetes insipidus (NDI), which is a disease characterized by a massive loss of water through the kidney and consequent severe dehydration. Dysregulation of AQP2 is also a cause of water retention with hyponatremia in heart failure, hepatic cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Antidiuretic hormone vasopressin is an upstream regulator of AQP2. Its binding to the vasopressin V2 receptor promotes AQP2 targeting to the apical membrane and thus enables water reabsorption. Tolvaptan, a vasopressin V2 receptor antagonist, is effective and widely used for water retention with hyponatremia. However, there are no studies showing improvement in hard outcomes or long-term prognosis. A possible reason is that vasopressin receptors have many downstream effects other than AQP2 function. It is expected that the development of drugs that directly target AQP2 may result in increased treatment specificity and effectiveness for water balance disorders. This review summarizes recent progress in studies of AQP2 and drug development challenges for water balance disorders.
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- 2021
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3. Wnt5a induces renal AQP2 expression by activating calcineurin signalling pathway
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Fumiaki Ando, Eisei Sohara, Tetsuji Morimoto, Naofumi Yui, Naohiro Nomura, Eriko Kikuchi, Daiei Takahashi, Takayasu Mori, Alain Vandewalle, Tatemitsu Rai, Sei Sasaki, Yoshiaki Kondo, and Shinichi Uchida
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Science - Abstract
The water channel AQP2 mediates the concentration of urine in the kidney. Here Ando et al. show that Wnt5 promotes collecting duct permeability by regulating AQP2 expression and localization through activation of the calmodulin/calcineurin signalling pathway.
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- 2016
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4. Generation and analysis of knock-in mice carrying pseudohypoaldosteronism type II-causing mutations in the cullin 3 gene
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Yuya Araki, Tatemitsu Rai, Eisei Sohara, Takayasu Mori, Yuichi Inoue, Kiyoshi Isobe, Eriko Kikuchi, Akihito Ohta, Sei Sasaki, and Shinichi Uchida
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Cullin 3 ,PHAII ,Hypertension ,Science ,Biology (General) ,QH301-705.5 - Abstract
Pseudohypoaldosteronism type II (PHAII) is a hereditary hypertensive disease caused by mutations in four different genes: with-no-lysine kinases (WNK) 1 and 4, Kelch-like family member 3 (KLHL3), and cullin 3 (Cul3). Cul3 and KLHL3 form an E3 ligase complex that ubiquitinates and reduces the expression level of WNK4. PHAII-causing mutations in WNK4 and KLHL3 impair WNK4 ubiquitination. However, the molecular pathogenesis of PHAII caused by Cul3 mutations is unclear. In cultured cells and human leukocytes, PHAII-causing Cul3 mutations result in the skipping of exon 9, producing mutant Cul3 protein lacking 57 amino acids. However, whether this phenomenon occurs in the kidneys and is responsible for the pathogenesis of PHAII in vivo is unknown. We generated knock-in mice carrying a mutation in the C-terminus of intron 8 of Cul3, c.1207−1G>A, which corresponds to a PHAII-causing mutation in the human Cul3 gene. Heterozygous Cul3G(−1)A/+ knock-in mice did not exhibit PHAII phenotypes, and the skipping of exon 9 was not evident in their kidneys. However, the level of Cul3 mRNA expression in the kidneys of heterozygous knock-in mice was approximately half that of wild-type mice. Furthermore, homozygous knock-in mice were nonviable. It suggested that the mutant allele behaved like a knockout allele and did not produce Cul3 mRNA lacking exon 9. A reduction in Cul3 expression alone was not sufficient to develop PHAII in the knock-in mice. Our findings highlighted the pathogenic role of mutant Cul3 protein and provided insight to explain why PHAII-causing mutations in Cul3 cause kidney-predominant PHAII phenotypes.
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- 2015
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5. Prognosis of chronic kidney disease with normal-range proteinuria: The CKD-ROUTE study.
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Soichiro Iimori, Shotaro Naito, Yumi Noda, Hidehiko Sato, Naohiro Nomura, Eisei Sohara, Tomokazu Okado, Sei Sasaki, Shinichi Uchida, and Tatemitsu Rai
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Medicine ,Science - Abstract
Although lower estimated glomerular filtration rate (eGFR) and higher proteinuria are high risks for mortality and kidney outcomes, the prognosis of chronic kidney disease (CKD) in patients with normal-range proteinuria remains unclear.In this prospective cohort study, 1138 newly visiting stage G2-G5 CKD patients were stratified into normal-range and abnormal-range proteinuria groups. Study endpoints were CKD progression (>50% eGFR loss or initiation of dialysis), cardiovascular events, and all-cause death.In total, 927 patients who were followed for >6 months were included in the analysis. The mean age was 67 years, and 70.2% were male. During a median follow-up of 35 months, CKD progression, cardiovascular events, and mortality were observed in 223, 110, and 55 patients, respectively. Patients with normal-range proteinuria had a significantly lower risk for CKD progression (hazard ratio, 0.20; 95% confidence interval, 0.10-0.38) than those with abnormal-proteinuria by multivariate Cox proportional hazard analysis. We also analyzed patients with normal-range proteinuria (n = 351). Nephrosclerosis was the most frequent cause of CKD among all patients with normal-range proteinuria (59.7%). During a median follow-up of 36 months, CKD progression, cardiovascular events, and mortality were observed in 10, 28, and 18 patients, respectively. The Kaplan-Meyer analysis demonstrated that the risks of CKD progression and cardiovascular events were not significantly different among CKD stages, whereas the risk of death was significantly higher in patients with advanced-stage CKD. Multivariate Cox proportional hazard analysis showed that the risk of three endpoints did not significantly differ among CKD stages.Newly visiting CKD patients with normal-range proteinuria, who tend to be overlooked during health checkups did not exhibit a decrease in kidney function even in advanced CKD stages under specialized nephrology care.
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- 2018
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6. Functional coupling of chloride–proton exchanger ClC-5 to gastric H+,K+-ATPase
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Yuji Takahashi, Takuto Fujii, Kyosuke Fujita, Takahiro Shimizu, Taiga Higuchi, Yoshiaki Tabuchi, Hisato Sakamoto, Ichiro Naito, Koji Manabe, Shinichi Uchida, Sei Sasaki, Akira Ikari, Kazuhiro Tsukada, and Hideki Sakai
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ClC-5 ,H+,K+-ATPase ,Gastric acid ,Tubulovesicle ,Parietal cell ,Science ,Biology (General) ,QH301-705.5 - Abstract
Summary It has been reported that chloride–proton exchanger ClC-5 and vacuolar-type H+-ATPase are essential for endosomal acidification in the renal proximal cells. Here, we found that ClC-5 is expressed in the gastric parietal cells which secrete actively hydrochloric acid at the luminal region of the gland, and that it is partially localized in the intracellular tubulovesicles in which gastric H+,K+-ATPase is abundantly expressed. ClC-5 was co-immunoprecipitated with H+,K+-ATPase in the lysate of tubulovesicles. The ATP-dependent uptake of 36Cl− into the vesicles was abolished by 2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile (SCH28080), an inhibitor of H+,K+-ATPase, suggesting functional expression of ClC-5. In the tetracycline-regulated expression system of ClC-5 in the HEK293 cells stably expressing gastric H+,K+-ATPase, ClC-5 was co-immunoprecipitated with H+,K+-ATPase, but not with endogenous Na+,K+-ATPase. The SCH28080-sensitive 36Cl− transporting activity was observed in the ClC-5-expressing cells, but not in the ClC-5-non-expressing cells. The mutant (E211A-ClC-5), which has no H+ transport activity, did not show the SCH28080-sensitive 36Cl− transport. On the other hand, both ClC-5 and its mutant (E211A) significantly increased the activity of H+,K+-ATPase. Our results suggest that ClC-5 and H+,K+-ATPase are functionally associated and that they may contribute to gastric acid secretion.
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- 2013
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7. Impaired KLHL3-Mediated Ubiquitination of WNK4 Causes Human Hypertension
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Mai Wakabayashi, Takayasu Mori, Kiyoshi Isobe, Eisei Sohara, Koichiro Susa, Yuya Araki, Motoko Chiga, Eriko Kikuchi, Naohiro Nomura, Yutaro Mori, Hiroshi Matsuo, Tomohiro Murata, Shinsuke Nomura, Takako Asano, Hiroyuki Kawaguchi, Shigeaki Nonoyama, Tatemitsu Rai, Sei Sasaki, and Shinichi Uchida
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Biology (General) ,QH301-705.5 - Abstract
Mutations in WNK kinases cause the human hypertensive disease pseudohypoaldosteronism type II (PHAII), but the regulatory mechanisms of the WNK kinases are not well understood. Mutations in kelch-like 3 (KLHL3) and Cullin3 were also recently identified as causing PHAII. Therefore, new insights into the mechanisms of human hypertension can be gained by determining how these components interact and how they are involved in the pathogenesis of PHAII. Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein. Transgenic mice overexpressing WNK4 showed PHAII phenotypes, and WNK4 protein was indeed increased in Wnk4D561A/+ PHAII model mice. Thus, WNK4 is a target for KLHL3-mediated ubiquitination, and the impaired ubiquitination of WNK4 is a common mechanism of human hereditary hypertension.
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- 2013
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8. A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo
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Katsuyuki Oi, Eisei Sohara, Tatemitsu Rai, Moko Misawa, Motoko Chiga, Dario R. Alessi, Sei Sasaki, and Shinichi Uchida
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Na-K-Cl cotransporter ,Na-Cl cotransporter ,WNK3 ,mouse kidney ,WNK ,Science ,Biology (General) ,QH301-705.5 - Abstract
Summary Mutations in WNK1 and WNK4 kinase genes have been shown to cause a human hereditary hypertensive disease, pseudohypoaldosteronism type II (PHAII). We previously discovered that WNK kinases phosphorylate and activate OSR1/SPAK kinases that regulate renal SLC12A family transporters such as NKCC2 and NCC, and clarified that the constitutive activation of this cascade causes PHAII. WNK3, another member of the WNK kinase family, was reported to be a strong activator of NCC/NKCC2 when assayed in Xenopus oocytes, suggesting that WNK3 also plays a major role in regulating blood pressure and sodium reabsorption in the kidney. However, it remains to be determined whether WNK3 is in fact involved in the regulation of these transporters in vivo. To clarify this issue, we generated and analyzed WNK3 knockout mice. Surprisingly, phosphorylation and expression of OSR1, SPAK, NKCC2 and NCC did not decrease in knockout mouse kidney under normal and low-salt diets. Similarly, expression of epithelial Na channel and Na/H exchanger 3 were not affected in knockout mice. Na+ and K+ excretion in urine in WNK3 knockout mice was not affected under different salt diets. Blood pressure in WNK3 knockout mice was not lower under normal diet. However, lower blood pressure was observed in WNK3 knockout mice fed low-salt diet. WNK4 and WNK1 expression was slightly elevated in the knockout mice under low-salt diet, suggesting compensation for WNK3 knockout by these WNKs. Thus, WNK3 may have some role in the WNK-OSR1/SPAK-NCC/NKCC2 signal cascade in the kidney, but its contribution to total WNK kinase activity may be minimal.
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- 2012
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9. Molecular Mechanisms and Drug Development in Aquaporin Water Channel Diseases: Aquaporin Superfamily (Superaquaporins): Expansion of Aquaporins Restricted to Multicellular Organisms
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Yoshiyuki Morishita, Yasuji Sakube, Sei Sasaki, and Kenichi Ishibashi
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Eleven aquaporins are identified in mammals. They all have highly conserved two asparagine-proline-alanine (NPA) boxes that are important for the formation of the water permeating pore. Recently we identified two new proteins in mammals distantly related to aquaporins (AQPs) with poorly conserved NPA boxes. Similarly poorly conserved AQP-like proteins were found in several genome projects of multicellular organisms. They may be subgrouped as the AQP superfamily or superaquaporins. Their function is still unknown. AQP11 knockout mice suffer from polycystic kidneys and neonatal fatality. The identification of superaquaporins will provide new insights into the role of AQPs in organogenesis. Keywords:: aquaporin, asparagine-proline-alanine (NPA) box, knockout mice, polycystic kidney
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- 2004
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10. Molecular Mechanisms and Drug Development in Aquaporin Water Channel Diseases: Molecular Mechanism of Water Channel Aquaporin-2 Trafficking
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Yumi Noda and Sei Sasaki
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Targeted positioning of water channel aquaporin-2 (AQP2) strictly regulates body water homeostasis. Trafficking of AQP2 to the apical membrane is critical for the reabsorption of water in renal collecting ducts. Besides the cAMP-mediated effect of vasopressin on AQP2 trafficking to the apical membrane, other signaling cascades also induce this sorting. Recently, AQP2-binding proteins that directly regulate this trafficking have been uncovered: SPA-1, a GTPase-activating protein (GAP) for Rap1, and cytoskeletal protein actin. This review summarizes recent advances related to the trafficking mechanism of AQP2 and its defect causing nephrogenic diabetes insipidus (NDI). Keywords:: aquaporin-2, PKA phosphorylation, missorting, Rho, cytoskeleton
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- 2004
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11. SPAK deficiency corrects pseudohypoaldosteronism II caused by WNK4 mutation.
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Pei-Yi Chu, Chih-Jen Cheng, Yi-Chang Wu, Yu-Wei Fang, Tom Chau, Shinichi Uchida, Sei Sasaki, Sung-Sen Yang, and Shih-Hua Lin
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Medicine ,Science - Abstract
Stimulation of the OSR1 (Oxidative stress-responsive kinase-1)/SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase]-NCC (Na(+)-Cl(-) cotransporter) signaling cascade plays an important role in the WNK [With-No-Lysine (K)] kinase 4 D561A knock-in mouse model of pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. The aim of this study was to investigate the respective roles of Osr1 and Spak in the pathogenesis of PHA II in vivo. Wnk4 (D561A/+) mice were crossed with kidney tubule-specific (KSP) Osr1 knockout (KSP-Osr1 (-/-)) and Spak knockout (Spak (-/-)) mice. Blood pressure, plasma and urine biochemistries, and the relevant protein expression in the kidneys were examined. Wnk4 (D561A/+), KSP-Osr1 (-/-), and Spak (-/-) mice recapitulated the phenotypes of PHA II, Bartter-like syndrome, and Gitelman syndrome, respectively. Wnk4 (D561A/+).KSP-Osr1 (-/-) remained phenotypically PHA II while Wnk4 (D561A/+).Spak (-/-) mice became normotensive and lacked the PHA II phenotype. Phosphorylated Spak and Ncc were similarly increased in both Wnk4 (D561A/+) and Wnk4 (D561A/+).KSP-Osr1 (-/-) mice while phosphorylated Ncc normalized in Wnk4 (D561A/+).Spak (-/-) mice. Furthermore, Wnk4 (D561A/+).KSP-Osr1 (-/-) mice exhibited exaggerated salt excretion in response to thiazide diuretics while Wnk4 (D561A/+).Spak (-/-) mice exhibited normal responses. Wnk4(D561A/+).Spak (-/-).KSP-Osr1 (-/-) triple mutant mice had low blood pressure and diminished phosphorylated Ncc. Both SPAK and OSR1 are important in the maintenance of blood pressure but activation of SPAK-NCC plays the dominant role in PHA II. SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation.
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- 2013
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12. Disruption of Membranes of Extracellular Vesicles Is Necessary for ELISA Determination of Urine AQP2: Proof of Disruption and Epitopes of AQP2 Antibodies
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Masaaki Nameta, Yoko Saijo, Yasukazu Ohmoto, Kiyonori Katsuragi, Keiko Yamamoto, Tadashi Yamamoto, Kenichi Ishibashi, and Sei Sasaki
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aquaporin-2 (AQP2) ,exosome ,extracellular vesicle ,ELISA ,biomarker ,kidney ,water-balance ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Aquaporin-2 (AQP2) is present in urine extracellular vesicles (EVs) and is a useful biomarker for water balance disorders. We previously found that pre-treatment of urine with alkali/detergent or storage at −25 °C is required for enzyme-linked immunosorbent assay (ELISA) measurement. We speculated that disruptions of EVs membranes are necessary to allow for the direct contact of antibodies with their epitopes. Human urine EVs were prepared using an ultracentrifugation method. Urine EV samples were stored at different temperatures for a week. Electron microscopy showed abundant EVs with diameters of 20–100 nm, consistent with those of exosomes, in normal urine, whereas samples from alkali/detergent pre-treated urine showed fewer EVs with large swollen shapes and frequent membrane disruptions. The abundance and structures of EVs were maintained during storage at −80 °C, but were severely damaged at −25 °C. Binding and competitive inhibition assays showed that epitopes of monoclonal antibody and polyclonal antibody were the hydrophilic Loop D and C-terminus of AQP2, respectively, both of which are present on the inner surface of EVs. Thus, urine storage at −25 °C or pre-treatment with alkali/detergent disrupt EVs membranes and allow AQP2 antibodies to bind to their epitopes located inside EVs.
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- 2016
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13. Acute insulin stimulation induces phosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney.
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Eisei Sohara, Tatemitsu Rai, Sung-Sen Yang, Akihito Ohta, Shotaro Naito, Motoko Chiga, Naohiro Nomura, Shih-Hua Lin, Alain Vandewalle, Eriko Ohta, Sei Sasaki, and Shinichi Uchida
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Medicine ,Science - Abstract
The NaCl cotransporter (NCC) is essential for sodium reabsorption at the distal convoluted tubules (DCT), and its phosphorylation increases its transport activity and apical membrane localization. Although insulin has been reported to increase sodium reabsorption in the kidney, the linkage between insulin and NCC phosphorylation has not yet been investigated. This study examined whether insulin regulates NCC phosphorylation. In cultured mpkDCT cells, insulin increased phosphorylation of STE20/SPS1-related proline-alanine-rich kinase (SPAK) and NCC in a dose-dependent manner. This insulin-induced phosphorylation of NCC was suppressed in WNK4 and SPAK knockdown cells. In addition, Ly294002, a PI3K inhibitor, decreased the insulin effect on SPAK and NCC phosphorylation, indicating that insulin induces phosphorylation of SPAK and NCC through PI3K and WNK4 in mpkDCT cells. Moreover, acute insulin administration to mice increased phosphorylation of oxidative stress-responsive kinase-1 (OSR1), SPAK and NCC in the kidney. Time-course experiments in mpkDCT cells and mice suggested that SPAK is upstream of NCC in this insulin-induced NCC phosphorylation mechanism, which was confirmed by the lack of insulin-induced NCC phosphorylation in SPAK knockout mice. Moreover, insulin administration to WNK4 hypomorphic mice did not increase phosphorylation of OSR1, SPAK and NCC in the kidney, suggesting that WNK4 is also involved in the insulin-induced OSR1, SPAK and NCC phosphorylation mechanism in vivo. The present results demonstrated that insulin is a potent regulator of NCC phosphorylation in the kidney, and that WNK4 and SPAK are involved in this mechanism of NCC phosphorylation by insulin.
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- 2011
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14. LRBA is essential for urinary concentration and body water homeostasis
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Yu Hara, Fumiaki Ando, Daisuke Oikawa, Koichiro Ichimura, Hideki Yanagawa, Yuriko Sakamaki, Azuma Nanamatsu, Tamami Fujiki, Shuichi Mori, Soichiro Suzuki, Naofumi Yui, Shintaro Mandai, Koichiro Susa, Takayasu Mori, Eisei Sohara, Tatemitsu Rai, Mikiko Takahashi, Sei Sasaki, Hiroyuki Kagechika, Fuminori Tokunaga, and Shinichi Uchida
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Mice ,Aquaporin 2 ,Multidisciplinary ,Body Water ,A Kinase Anchor Proteins ,Animals ,Homeostasis ,Phosphorylation ,Cyclic AMP-Dependent Protein Kinases ,Adaptor Proteins, Signal Transducing - Abstract
Protein kinase A (PKA) directly phosphorylates aquaporin-2 (AQP2) water channels in renal collecting ducts to reabsorb water from urine for the maintenance of systemic water homeostasis. More than 50 functionally distinct PKA-anchoring proteins (AKAPs) respectively create compartmentalized PKA signaling to determine the substrate specificity of PKA. Identification of an AKAP responsible for AQP2 phosphorylation is an essential step toward elucidating the molecular mechanisms of urinary concentration. PKA activation by several compounds is a novel screening strategy to uncover PKA substrates whose phosphorylation levels were nearly perfectly correlated with that of AQP2. The leading candidate in this assay proved to be an AKAP termed lipopolysaccharide-responsive and beige-like anchor protein (LRBA). We found that LRBA colocalized with AQP2 in vivo, and Lrba knockout mice displayed a polyuric phenotype with severely impaired AQP2 phosphorylation. Most of the PKA substrates other than AQP2 were adequately phosphorylated by PKA in the absence of LRBA, demonstrating that LRBA-anchored PKA preferentially phosphorylated AQP2 in renal collecting ducts. Furthermore, the LRBA–PKA interaction, rather than other AKAP–PKA interactions, was robustly dissociated by PKA activation. AKAP–PKA interaction inhibitors have attracted attention for their ability to directly phosphorylate AQP2. Therefore, the LRBA–PKA interaction is a promising drug target for the development of anti-aquaretics.
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- 2022
15. Minimal change disease concurrent with acute interstitial nephritis after long-term use of sorafenib in a patient with renal cell carcinoma
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Hidenori Nishida, Tatemitsu Rai, Shinichi Uchida, Sei Sasaki, and Katsuhito Ihara
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Nephrology ,Sorafenib ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,030232 urology & nephrology ,Urology ,Case Report ,General Medicine ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,Internal medicine ,medicine ,Prednisolone ,Minimal change disease ,Renal biopsy ,Acute tubulointerstitial nephritis ,business ,Nephrotic syndrome ,medicine.drug - Abstract
Sorafenib is one of the multi-targeted tyrosine kinase inhibitors (TKI), mainly used for treating advanced renal cell carcinoma. Accumulated evidence indicates a minority of patients develop nephrotic syndrome (NS) as a high-grade nephrotoxic injury; however, evidence of NS after long-term use of sorafenib remains unclear. A 64-year-old man developed NS following 2-year use of sorafenib and his NS persisted even after sorafenib use was discontinued. Renal biopsy disclosed minimal change disease (MCD) concurrent with acute tubulointerstitial nephritis, indicating secondary MCD with which sorafenib may be involved. To prevent permanent renal insufficiency, we administered glucocorticoid and succeeded in achieving complete remission from NS. Nephrotoxic injuries could occur at any time with variable onset after sorafenib. Renal biopsy should be pursued in the case of NS associated with TKI therapy. To facilitate recovery of renal dysfunction, administration of prednisolone should be considered, particularly when NS does not disappear after cessation of TKIs.
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- 2021
16. A Prospective Randomized, Multicenter Trial Evaluating the Efficacy and Safety of Combined Therapy with Pirfenidone and Inhaled N-Acetylcysteine for Idiopathic Pulmonary Fibrosis
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Yoshinori Tanino, Kazuhisa Takahashi, Yoshio Taguchi, Yasuhiro Kondoh, Hajime Takizawa, Fumikazu Sakai, T. Kishaba, T. Suda, T. Saito, Sakae Homma, Masashi Bando, Noboru Hattori, K. Kataoka, Sei Sasaki, K. Kishi, Susumu Sakamoto, Hiroshi Mukae, Naohiko Inase, Kazuyoshi Kuwano, Takeshi Johkoh, Yasuhiko Nishioka, Tomoaki Hoshino, and T. Kido
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Acetylcysteine ,medicine.medical_specialty ,Idiopathic pulmonary fibrosis ,business.industry ,Multicenter trial ,Internal medicine ,medicine ,Combined therapy ,Pirfenidone ,business ,medicine.disease ,Gastroenterology ,medicine.drug - Published
- 2020
17. AQP2 in human urine is predominantly localized to exosomes with preserved water channel activities
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Saki Mikami, Tadashi Yamamoto, Keiko Yamamoto, Yuko Miyazawa, Tatsuya Saito, Masaki Sakai, Kenichi Ishibashi, and Sei Sasaki
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0301 basic medicine ,Differential centrifugation ,medicine.medical_specialty ,Kidney ,Water transport ,urogenital system ,Physiology ,Endosome ,business.industry ,Immunoprecipitation ,urologic and male genital diseases ,ESCRT ,Microvesicles ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Nephrology ,Physiology (medical) ,Internal medicine ,Medicine ,Centrifugation ,business ,030217 neurology & neurosurgery - Abstract
AQP2 water channel is critical for urinary concentration in the kidney. Interestingly, AQP2 is abundantly excreted in the urine as extracellular vesicles (EVs), which is known to be a useful biomarker for water-balance disorders although the character of AQP2-enriched EVs is poorly understood including water channel function. Human urine EVs were obtained by a differential centrifugation method. AQP2-bearing EVs were isolated by immunoprecipitation with an AQP2-specific antibody, and the proteins in the EVs were analyzed by LC–MS/MS proteomic analysis. Osmotic water permeability (Pf) of the AQP2-rich EVs was measured by a stopped-flow method monitoring scattered light intensity in response to outwardly directed osmotic gradient. Sequential centrifugation of human urine showed that AQP2 was present predominantly (80%) in low-density EVs (160,000 g), whereas negligible amount in high-density EVs (17,000 g). Proteomic analysis of the AQP2-bearing EVs identified 137 proteins, mostly in the endosome pathway, including the components of ESCRT (endosomal sorting complex required transporter)-I, II, III. Pf value of the 160,000 g EVs was 4.75 ± 0.38 × 10−4 cm s−1 (mean ± SE) with the activation energy of 3.51 kcal mol−1 which was inhibited with 0.3 mM HgCl2 by 63%, suggesting a channel-mediated water transport. Moreover, Pf value showed a significant correlation with the abundance of AQP2 protein in EVs. Taken together, AQP2 is localized predominantly to urinary exosomes with preserved water channel activities.
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- 2018
18. Introduction of arteriovenous grafts with graft insertion anastomosis for hemodialysis access
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Takuya Hatakeyama, Hiroyuki Okamoto, Tatsu Nakazawa, Masanobu Hoshino, Sei Sasaki, and Tatsuya Nonaka
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Percutaneous ,Brachial Artery ,medicine.medical_treatment ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,Anastomosis ,Prosthesis ,Veins ,Blood Vessel Prosthesis Implantation ,03 medical and health sciences ,Arteriovenous Shunt, Surgical ,0302 clinical medicine ,Suture (anatomy) ,Forearm ,Renal Dialysis ,Blood vessel prosthesis ,medicine ,Humans ,Vascular Patency ,Vein ,Aged ,Aged, 80 and over ,business.industry ,Anastomosis, Surgical ,Suture Techniques ,Graft Occlusion, Vascular ,Middle Aged ,Blood Vessel Prosthesis ,Surgery ,Treatment Outcome ,medicine.anatomical_structure ,Female ,Cardiology and Cardiovascular Medicine ,business ,Angioplasty, Balloon - Abstract
Objective An arteriovenous bridging graft is a viable option for patients with compromised arteries or veins because of advanced age or diabetes. Arteriovenous graft with graft insertion anastomosis (AVGI) is the novel technique for graft-vein anastomosis where the prosthesis is inserted into the vein, and the anastomosis is performed on the surface of the prosthesis. This study assessed the short-term and long-term results of AVGI to clarify the efficacy of this technique. Methods Between 2010 and 2015, AVGI was performed in graft-vein anastomosis of prosthetic forearm loop access. Characteristics and level of complications were assessed. To evaluate the long-term results, functional graft patency and frequency of percutaneous transluminal angioplasty were examined. Results The study comprised 58 patients. There were no deaths related to the surgery. The time of hemostasis after AVGI was recorded at 0 seconds because no bleeding from the suture holes was seen. At 1, 2, and 3 years, primary patency were 45.1% ± 7.5%, 23.1% ± 7.5%, and 23.1% ± 7.5%, respectively, and assisted primary patency rates were 59.4% ± 7.2%, 50.8% ± 7.6%, and 50.8% ± 7.6%, respectively. Secondary patency rates at 4 and 5 years were 100% ± 0% and 94.1% ± 5.7%, respectively. The frequency of percutaneous balloon angioplasty to maintain the patency was 1.61 ± 0.53 times per year. Graft infection occurred in four patients (6.9%). Conclusions AVGI is an advantageous technique for graft vein anastomosis in an arteriovenous bridging graft in both the short-term and long-term.
- Published
- 2017
19. Ser-261 phospho-regulation is involved in pS256 and pS269-mediated aquaporin-2 apical translocation
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Shinichi Uchida, Sei Sasaki, Naofumi Yui, and Fumiaki Ando
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0301 basic medicine ,030232 urology & nephrology ,Biophysics ,Chromosomal translocation ,Stimulation ,Biology ,urologic and male genital diseases ,Biochemistry ,Madin Darby Canine Kidney Cells ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,0302 clinical medicine ,Serine ,Animals ,Phosphorylation ,Molecular Biology ,Aquaporin 2 ,Forskolin ,urogenital system ,Cell Membrane ,Colforsin ,Cell Biology ,Apical membrane ,Endocytosis ,Rats ,Cell biology ,Protein Transport ,030104 developmental biology ,Transcytosis ,chemistry ,Intracellular - Abstract
Vasopressin catalyzes aquaporin-2 phosphorylation at several serine sites in the C-terminal region. Compared with Ser-256 and Ser-269 phosphorylation, the role of Ser-261 phospho-regulation on vasopressin-regulated AQP2 apical translocation is largely unknown. In addition, recent discovery of transcytotic apical delivery of AQP2 made the concept of its intracellular trafficking even more complicated. In this study, we evaluated how intact phospho-AQP2 signals fit with the transcytosis trafficking model in Madin-Darby canine kidney cells. PS256 and pS269 signals were intracellularly detectable in wild-type AQP2 at the beginning of forskolin stimulation (1 min). These phospho-signals were detectable in basolateral membranes even after 10 min of stimulation. AQP2 stably inserted in the apical membrane increased pS269 and decreased pS261 signals. In an NDI-causing mutant P262L-AQP2, in which Ser-261 phospho-regulation is impaired, the pS256 and pS269 signals were detectable in the basolateral membranes with increased pS261 signals after forskolin stimulation. These results suggest that Ser-261 phospho-regulation is involved in pS256- and pS269-mediated AQP2 apical translocation.
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- 2017
20. TO029FUNCTIONAL AND PROTEINOUS CHARACTERIZATION OF AQP2-RICH EXTRACELLULAR VESICLES IN HUMAN URINE
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Tetsuya Saito, Yasuko Tanaka, Saki Mikami, Sei Sasaki, Tadashi Yamamoto, Keiko Yamamoto, Yuko Miyazawa, and Kenichi Ishibashi
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Transplantation ,Biochemistry ,Nephrology ,Aquaporin 2 ,business.industry ,Medicine ,Urine ,business ,Extracellular vesicles - Published
- 2017
21. Infective endocarditis in a patient with lupus nephritis who was undergoing immunosuppressive therapy: A case of survival
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Takayuki Toda, Sei Sasaki, Katsuhito Ihara, Shinichi Uchida, Tatemitsu Rai, Noriaki Matsui, and Shotaro Naito
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medicine.medical_specialty ,immunosuppressive therapy ,Lupus nephritis ,Case Report ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,systemic lupus erythematosus ,immune system diseases ,Internal medicine ,medicine ,In patient ,skin and connective tissue diseases ,Cardiac status ,lupus nephritis ,030203 arthritis & rheumatology ,Autoimmune disease ,medicine.diagnostic_test ,infective endocarditis ,business.industry ,Valvular regurgitation ,Patient survival ,medicine.disease ,Infective endocarditis ,Renal biopsy ,business - Abstract
Systemic lupus erythematosus is an autoimmune disease associated with mild valvular regurgitation. However, there have been no detailed reports of infective endocarditis in patients with systemic lupus erythematosus. Here, we describe a case of a 55-year-old woman without any cardiac abnormalities who was diagnosed with lupus nephritis by renal biopsy; she contracted infective endocarditis while receiving immunosuppressive therapy. Our case emphasizes that special consideration of the occurrence of infective endocarditis, and its early diagnosis and treatment are mandatory for patient survival. We propose that echocardiography should be performed before treating patients with systemic lupus erythematosus who have an uncertain cardiac status.
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- 2017
22. Aquaporin-2 Ser-261 phosphorylation is regulated in combination with Ser-256 and Ser-269 phosphorylation
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Sei Sasaki, Shinichi Uchida, and Naofumi Yui
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0301 basic medicine ,Vasopressin ,Vasopressins ,Immunoprecipitation ,Population ,030232 urology & nephrology ,Biophysics ,macromolecular substances ,Biology ,Kidney ,urologic and male genital diseases ,Biochemistry ,Cell Line ,Dephosphorylation ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,0302 clinical medicine ,Serine ,Animals ,Protein phosphorylation ,Phosphorylation ,education ,Molecular Biology ,education.field_of_study ,Aquaporin 2 ,Forskolin ,urogenital system ,Colforsin ,Cell Biology ,Molecular biology ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry - Abstract
Aquaporin-2 (AQP2) is a water channel in collecting duct principal cells in the kidney. Vasopressin catalyzes AQP2 phosphorylation at several serine sites in its C-terminus: Ser-256, Ser-261, and Ser-269. Upon stimulation by vasopressin, Ser-269 phosphorylation increases and Ser-261 phosphorylation decreases. Ser-256 phosphorylation is relatively constant. However, whether these types of phospho-regulation occur independently in distinct AQP2 populations or sequentially in the same AQP2 population is unclear. Especially, the manner of vasopressin-mediated Ser-261 phospho-regulation has been in controversy. In this study, we established phospho-specific AQP2 immunoprecipitation assays and investigated how pS256-positive AQP2 and pS269-positive AQP2 are catalyzed by forskolin or vasopressin, focusing on their Ser-261 phosphorylation status in polarized Madin-Darby canine kidney (MDCK) cells and in mice. In forskolin-treated MDCK cells, Ser-269 phosphorylation preceded Ser-261 dephosphorylation and Ser-256 phosphorylation was constant. In both MDCK cells and mouse kidney, phospho-specific immunoprecipitation revealed that the regulated Ser-269 phosphorylation occurred in the pS256-positive AQP2 population. Importantly, basal-state Ser-261 phosphorylation and its regulated dephosphorylation occurred in the pS256- and pS269-positive AQP2 population. These results provide the direct evidence that the Ser-261 dephosphorylation is involved in the pS256- and pS269-related AQP2 regulation.
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- 2017
23. Murine colon proteome and characterization of the protein pathways.
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Sameh Magdeldin, Yutaka Yoshida, Huiping Li, Yoshitaka Maeda, Munesuke Yokoyama, Shymaa Enany, Ying Zhang, Bo Xu, Hidehiko Fujinaka, Eishin Yaoita, Sei Sasaki, and Tadashi Yamamoto
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- 2012
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24. Comprehensive genetic testing approach for major inherited kidney diseases, using next-generation sequencing with a custom panel
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Kazuyoshi Hosomichi, Shinichi Uchida, Takayasu Mori, Eisei Sohara, Hirofumi Nakaoka, Sei Sasaki, Ituro Inoue, Shintaro Mandai, Tomokazu Okado, Motoko Chiga, and Tatemitsu Rai
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Adult ,Genetic Markers ,Male ,0301 basic medicine ,Candidate gene ,Heredity ,Adolescent ,Physiology ,DNA Mutational Analysis ,030232 urology & nephrology ,Disease ,DNA sequencing ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Predictive Value of Tests ,Physiology (medical) ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Child ,Genetic Association Studies ,Exome sequencing ,Aged ,Genetic testing ,Sanger sequencing ,Genetics ,medicine.diagnostic_test ,business.industry ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Infant ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Phenotype ,030104 developmental biology ,Nephrology ,Child, Preschool ,Mutation ,Hereditary Diseases ,symbols ,Female ,Kidney Diseases ,business ,Kidney disease - Abstract
Gene identification of hereditary kidney diseases by DNA sequencing is important for precise diagnosis, treatment, and genetic consultations. However, the conventional Sanger sequencing is now practically powerless in the face of ever increasing numbers of reported causative genes of various hereditary diseases. The advent of next-generation sequencing technology has enabled large-scale, genome-wide, simultaneous sequence analyses of multiple candidate genes. We designed and verified a comprehensive diagnosis panel for approximately 100 major inherited kidney diseases, including 127 known genes. The panel was named Simple, sPEedy and Efficient Diagnosis of Inherited KIdney Diseases (SPEEDI-KID). We applied the panel to 73 individuals, clinically diagnosed with an inherited kidney disease, from 56 families. The panel efficiently covered the candidate genes and allowed a prompt and accurate genetic diagnosis. Moreover, 18 unreported mutations suspected as the disease causes were detected. All these mutations were validated by Sanger sequencing, with 100 % concordance. In conclusion, we developed a powerful diagnostic method, focusing on inherited kidney diseases, using a custom panel, SPEEDI-KID, allowing a fast, easy, and comprehensive diagnosis regardless of the disease type.
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- 2016
25. Combination of low body mass index and serum albumin level is associated with chronic kidney disease progression: the chronic kidney disease-research of outcomes in treatment and epidemiology (CKD-ROUTE) study
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Yumi Noda, Soichiro Iimori, Shintaro Mandai, Eisei Sohara, Tomokazu Okado, Hiroaki Kikuchi, Eiichiro Kanda, Sei Sasaki, Shinichi Uchida, Katsuyuki Oi, Shotaro Naito, Tatemitsu Rai, Masanobu Akazawa, Takayuki Toda, and Teiichi Tamura
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Male ,Time Factors ,Physiology ,medicine.medical_treatment ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,Kidney ,Gastroenterology ,Body Mass Index ,0302 clinical medicine ,Risk Factors ,Odds Ratio ,Medicine ,Prospective Studies ,Hypoalbuminemia ,Prospective cohort study ,Aged, 80 and over ,biology ,Middle Aged ,Nephrology ,Disease Progression ,Female ,Glomerular Filtration Rate ,medicine.medical_specialty ,Serum albumin ,Down-Regulation ,Nutritional Status ,Renal function ,Serum Albumin, Human ,Protein-Energy Malnutrition ,03 medical and health sciences ,Thinness ,Renal Dialysis ,Physiology (medical) ,Internal medicine ,Humans ,Renal Insufficiency, Chronic ,Tokyo ,Serum Albumin ,Dialysis ,Aged ,Chi-Square Distribution ,business.industry ,Odds ratio ,medicine.disease ,Logistic Models ,Endocrinology ,Multivariate Analysis ,Linear Models ,biology.protein ,business ,Body mass index ,Biomarkers ,Kidney disease - Abstract
The relationship between protein–energy wasting and chronic kidney disease (CKD) progression is unknown. In the present prospective cohort study, we evaluated the hypothesis that a combination of low body mass index (BMI) and serum albumin level is associated with rapid CKD progression. The study cohort comprised 728 predialysis Japanese patients with CKD (stages 2–5) enrolled from 2010 to 2011. Patients were categorized into four groups according to their serum albumin levels and BMI: group 1, low serum albumin level (
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- 2016
26. Generation and analysis of knock-in mice carrying pseudohypoaldosteronism type II-causing mutations in the cullin 3 gene
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Eisei Sohara, Sei Sasaki, Tatemitsu Rai, Yuichi Inoue, Kiyoshi Isobe, Akihito Ohta, Takayasu Mori, Shinichi Uchida, Eriko Kikuchi, and Yuya Araki
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Genetics ,Mutation ,QH301-705.5 ,Science ,Mutant ,Pseudohypoaldosteronism ,Biology ,medicine.disease_cause ,medicine.disease ,Molecular biology ,General Biochemistry, Genetics and Molecular Biology ,WNK4 ,Exon ,Cullin 3 ,Gene knockin ,Hypertension ,medicine ,PHAII ,Allele ,Biology (General) ,General Agricultural and Biological Sciences ,Gene ,Research Article - Abstract
Pseudohypoaldosteronism type II (PHAII) is a hereditary hypertensive disease caused by mutations in four different genes: with-no-lysine kinases (WNK) 1 and 4, Kelch-like family member 3 (KLHL3), and cullin 3 (Cul3). Cul3 and KLHL3 form an E3 ligase complex that ubiquitinates and reduces the expression level of WNK4. PHAII-causing mutations in WNK4 and KLHL3 impair WNK4 ubiquitination. However, the molecular pathogenesis of PHAII caused by Cul3 mutations is unclear. In cultured cells and human leukocytes, PHAII-causing Cul3 mutations result in the skipping of exon 9, producing mutant Cul3 protein lacking 57 amino acids. However, whether this phenomenon occurs in the kidneys and is responsible for the pathogenesis of PHAII in vivo is unknown. We generated knock-in mice carrying a mutation in the C-terminus of intron 8 of Cul3, c.1207−1G>A, which corresponds to a PHAII-causing mutation in the human Cul3 gene. Heterozygous Cul3G(−1)A/+ knock-in mice did not exhibit PHAII phenotypes, and the skipping of exon 9 was not evident in their kidneys. However, the level of Cul3 mRNA expression in the kidneys of heterozygous knock-in mice was approximately half that of wild-type mice. Furthermore, homozygous knock-in mice were nonviable. It suggested that the mutant allele behaved like a knockout allele and did not produce Cul3 mRNA lacking exon 9. A reduction in Cul3 expression alone was not sufficient to develop PHAII in the knock-in mice. Our findings highlighted the pathogenic role of mutant Cul3 protein and provided insight to explain why PHAII-causing mutations in Cul3 cause kidney-predominant PHAII phenotypes., Summary: A knock-in mutation in intron 8 of Cul3 in mice led to decreased Cul3 protein expression. Decreased Cul3 protein expression alone did not cause pseudohypoaldosteronism type II (PHAII).
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- 2015
27. AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus
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Shinichi Uchida, Fumiaki Ando, Tatemitsu Rai, Naofumi Yui, Tetsuji Morimoto, Hiroyuki Kagechika, Eisei Sohara, Yoshiaki Kondo, Naohiro Nomura, Shuichi Mori, and Sei Sasaki
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Male ,0301 basic medicine ,Receptors, Vasopressin ,Vasopressin ,A Kinase Anchor Proteins ,General Physics and Astronomy ,Diabetes Insipidus, Nephrogenic ,chemistry.chemical_compound ,0302 clinical medicine ,Cyclic AMP ,lcsh:Science ,Cell Line, Transformed ,Multidisciplinary ,Chemistry ,Aquaporin 2 ,030220 oncology & carcinogenesis ,Urine osmolality ,Protein Binding ,medicine.medical_specialty ,Science ,Context (language use) ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Phenols ,Internal medicine ,medicine ,Animals ,Humans ,Cyclic adenosine monophosphate ,Amino Acid Sequence ,Benzhydryl Compounds ,Kidney Tubules, Collecting ,Osmolar Concentration ,Water ,Epithelial Cells ,General Chemistry ,Benzazepines ,Nephrogenic diabetes insipidus ,medicine.disease ,Cyclic AMP-Dependent Protein Kinases ,Arginine Vasopressin ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Tolvaptan ,Diabetes insipidus ,lcsh:Q ,Chemical chaperone - Abstract
Congenital nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine. Congenital NDI is mainly caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R), leading to impaired aquaporin-2 (AQP2) water channel activity. So far, treatment options of congenital NDI either by rescuing mutant V2R with chemical chaperones or by elevating cyclic adenosine monophosphate (cAMP) levels have failed to yield effective therapies. Here we show that inhibition of A-kinase anchoring proteins (AKAPs) binding to PKA increases PKA activity and activates AQP2 channels in cortical collecting duct cells. In vivo, the low molecular weight compound 3,3′-diamino-4,4′-dihydroxydiphenylmethane (FMP-API-1) and its derivatives increase AQP2 activity to the same extent as vasopressin, and increase urine osmolality in the context of V2R inhibition. We therefore suggest that FMP-API-1 may constitute a promising lead compound for the treatment of congenital NDI caused by V2R mutations., Patients suffering from congenital nephrogenic diabetes insipidus (NDI) fail to concentrate urine due to mutations in vasopressin type 2 receptor (V2R). Here Ando et al. show that agents disrupting the interaction between PKA and AKAPs restore aquaporin-2 activity downstream of V2R, offering a therapeutic approach for the treatment of NDI.
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- 2018
28. Kelch-Like Protein 2 Mediates Angiotensin II–With No Lysine 3 Signaling in the Regulation of Vascular Tonus
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Fumiaki Ando, Katsuyuki Oi, Yuki Yoshizaki, Yuya Araki, Eisei Sohara, Sei Sasaki, Yuichi Inoue, Daiei Takahashi, Hidenori Nishida, Shinichi Uchida, Kiyoshi Isobe, Naohiro Nomura, Takayasu Mori, Tatemitsu Rai, Nobuhisa Morimoto, Yutaro Mori, and Moko Zeniya
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medicine.medical_specialty ,Vascular smooth muscle ,Myocytes, Smooth Muscle ,Nerve Tissue Proteins ,Protein Serine-Threonine Kinases ,Muscle, Smooth, Vascular ,Mice ,Sequestosome 1 ,Ubiquitin ,Internal medicine ,Sequestosome-1 Protein ,Autophagy ,medicine ,Animals ,Solute Carrier Family 12, Member 2 ,education ,Aorta ,Cells, Cultured ,Heat-Shock Proteins ,Adaptor Proteins, Signal Transducing ,education.field_of_study ,biology ,Kinase ,Angiotensin II ,Microfilament Proteins ,Sodium, Dietary ,General Medicine ,Ubiquitin ligase ,WNK4 ,Cell biology ,Basic Research ,Endocrinology ,Vasoconstriction ,Nephrology ,Gene Knockdown Techniques ,Muscle Tonus ,biology.protein ,Signal transduction ,Signal Transduction - Abstract
Recently, the kelch-like protein 3 (KLHL3)–Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease. However, the involvement of WNK kinase regulation by ubiquitination in situations other than PHAII has not been identified. Previously, we identified the WNK3–STE20/SPS1-related proline/alanine-rich kinase–Na/K/Cl cotransporter isoform 1 phosphorylation cascade in vascular smooth muscle cells and found that it constitutes an important mechanism of vascular constriction by angiotensin II (AngII). In this study, we investigated the involvement of KLHL proteins in AngII-induced WNK3 activation of vascular smooth muscle cells. In the mouse aorta and mouse vascular smooth muscle (MOVAS) cells, KLHL3 was not expressed, but KLHL2, the closest homolog of KLHL3, was expressed. Salt depletion and acute infusion of AngII decreased KLHL2 and increased WNK3 levels in the mouse aorta. Notably, the AngII-induced changes in KLHL2 and WNK3 expression occurred within minutes in MOVAS cells. Results of KLHL2 overexpression and knockdown experiments in MOVAS cells confirmed that KLHL2 is the major regulator of WNK3 protein abundance. The AngII-induced decrease in KLHL2 was not caused by decreased transcription but increased autophagy-mediated degradation. Furthermore, knockdown of sequestosome 1/p62 prevented the decrease in KLHL2, suggesting that the mechanism of KLHL2 autophagy could be selective autophagy mediated by sequestosome 1/p62. Thus, we identified a novel component of signal transduction in AngII-induced vascular contraction that could be a promising drug target.
- Published
- 2015
29. Anaemia management and mortality risk in newly visiting patients with chronic kidney disease in Japan: The CKD-ROUTE study
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Yumi Noda, Soichiro Iimori, Hidenori Nishida, Naofumi Yui, Tomokazu Okado, Sei Sasaki, Shinichi Uchida, Hiromi Kihira, Tatemitsu Rai, and Shotaro Naito
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Nephrology ,medicine.medical_specialty ,Pediatrics ,business.industry ,Hazard ratio ,General Medicine ,Iron deficiency ,Primary care ,medicine.disease ,Confidence interval ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Iron supplementation ,Prospective cohort study ,business ,Kidney disease - Abstract
Aim To investigate the association between iron deficiency anaemia and mortality risk and assess the changes in anaemia and iron status after primary management by a nephrologist. Methods In this prospective cohort study, we stratified 951 non-dialysis chronic kidney disease (CKD) G2–G5 patients newly visiting 16 nephrology centres into four groups according to the presence of anaemia with or without iron deficiency. All-cause mortality, cardiovascular (CV)-related mortality, and a change in anaemia and iron status after specialized primary care were the endpoints evaluated. Results During a median follow-up time of 19 months, the number of all-cause deaths and CV-related deaths were 56 and 26, respectively. Compared with the control group, the groups with isolated anaemia and iron deficiency anaemia had significantly higher all-cause mortalities (isolated anaemia: hazard ratio (HR), 3.37; 95% confidence intervals (CI), 1.76–6.44; iron deficiency anaemia: HR, 3.11; 95% CI, 1.21–8.01) and CV-related mortalities (isolated anaemia: HR, 3.64; 95% CI, 1.36–9.73; iron deficiency anaemia: HR, 3.86; 95% CI, 1.11–13.41). In the isolated anaemia group, erythropoietin-stimulating agent (ESA) prescriptions significantly increased to approximately 70%. However, in patients with both anaemia and iron deficiency, iron prescriptions only increased to 48.1%. Conclusions Iron deficiency anaemia and isolated anaemia were associated with all-cause and CV-related mortality. The absence of relative increase in iron prescriptions suggests that iron deficiency should be accurately assessed and iron supplementation should be appropriately used to manage anaemia in non-dialysis patients with CKD.
- Published
- 2015
30. Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters
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Shinya Fujii, Shinichi Uchida, Eriko Kikuchi, Tohru Mizushima, Eisei Sohara, Moko Zeniya, Sei Sasaki, Hiroyuki Kagechika, Kiyoshi Isobe, Mari Ishigami-Yuasa, Tomoaki Ishihara, Takayasu Mori, and Tatemitsu Rai
- Subjects
Cell signaling ,Sodium-Potassium-Chloride Symporters ,Enzyme-Linked Immunosorbent Assay ,Protein Serine-Threonine Kinases ,Pharmacology ,Salicylanilides ,Sensitivity and Specificity ,Minor Histocompatibility Antigens ,Mice ,Random Allocation ,WNK Lysine-Deficient Protein Kinase 1 ,Animals ,Medicine ,Phosphorylation ,Protein kinase A ,Antihypertensive Agents ,Ion Transport ,urogenital system ,business.industry ,Reabsorption ,Kinase ,General Medicine ,Antiparasitic agent ,Mice, Inbred C57BL ,Disease Models, Animal ,Basic Research ,Biochemistry ,Nephrology ,Hypertension ,Female ,Signal transduction ,business ,Cotransporter ,Signal Transduction - Abstract
Upon activation by with-no-lysine kinases, STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) phosphorylates and activates SLC12A transporters such as the Na(+)-Cl(-) cotransporter (NCC) and Na(+)-K(+)-2Cl(-) cotransporter type 1 (NKCC1) and type 2 (NKCC2); these transporters have important roles in regulating BP through NaCl reabsorption and vasoconstriction. SPAK knockout mice are viable and display hypotension with decreased activity (phosphorylation) of NCC and NKCC1 in the kidneys and aorta, respectively. Therefore, agents that inhibit SPAK activity could be a new class of antihypertensive drugs with dual actions (i.e., NaCl diuresis and vasodilation). In this study, we developed a new ELISA-based screening system to find novel SPAK inhibitors and screened >20,000 small-molecule compounds. Furthermore, we used a drug repositioning strategy to identify existing drugs that inhibit SPAK activity. As a result, we discovered one small-molecule compound (Stock 1S-14279) and an antiparasitic agent (Closantel) that inhibited SPAK-regulated phosphorylation and activation of NCC and NKCC1 in vitro and in mice. Notably, these compounds had structural similarity and inhibited SPAK in an ATP-insensitive manner. We propose that the two compounds found in this study may have great potential as novel antihypertensive drugs.
- Published
- 2015
31. Retroperitoneal Fibrosis in Chronic Kidney Disease
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Yuki Yoshizaki, Naofumi Yui, Junichi Ishigami, Shinichi Uchida, Tatemitsu Rai, Tomokazu Okado, Soichiro Iimori, Katusyuki Oi, Eisei Sohara, and Sei Sasaki
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Pathology ,medicine.medical_specialty ,business.industry ,Prednisolone ,Medicine ,IgG4-related disease ,medicine.symptom ,business ,medicine.disease ,Retroperitoneal fibrosis ,Kidney disease ,medicine.drug - Published
- 2015
32. Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model
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Jing Zhou, Shigeo Horie, Motoko Chiga, Sei Sasaki, Yuichi Inoue, Shinichi Uchida, Katsuki Kobayashi, Xuefeng Su, Kenichi Ishibashi, Eisei Sohara, and Tatemitsu Rai
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medicine.medical_specialty ,Glycosylation ,TRPP Cation Channels ,Genotype ,Transgene ,Immunoblotting ,Mice, Transgenic ,Biology ,Aquaporins ,Endoplasmic Reticulum ,Kidney ,Protein biotinylation ,Kidney Tubules, Proximal ,Mice ,Internal medicine ,medicine ,Polycystic kidney disease ,Animals ,Biotinylation ,Transgenes ,Mice, Knockout ,Polycystin-1 ,Polycystic Kidney Diseases ,PKD1 ,Endoplasmic reticulum ,Kidney metabolism ,General Medicine ,medicine.disease ,Cell biology ,Disease Models, Animal ,Basic Research ,Endocrinology ,medicine.anatomical_structure ,Nephrology ,Subcellular Fractions - Abstract
We previously reported that disruption of the aquaporin-11 (AQP11) gene in mice resulted in cystogenesis in the kidney. In this study, we aimed to clarify the mechanism of cystogenesis in AQP11(-/-) mice. To enable the analyses of AQP11 at the protein level in vivo, AQP11 BAC transgenic mice (Tg(AQP11)) that express 3×HA-tagged AQP11 protein were generated. This AQP11 localized to the endoplasmic reticulum (ER) of proximal tubule cells in Tg(AQP11) mice and rescued renal cystogenesis in AQP11(-/-) mice. Therefore, we hypothesized that the absence of AQP11 in the ER could result in impaired quality control and aberrant trafficking of polycystin-1 (PC-1) and polycystin-2 (PC-2). Compared with kidneys of wild-type mice, AQP11(-/-) kidneys exhibited increased protein expression levels of PC-1 and decreased protein expression levels of PC-2. Moreover, PC-1 isolated from AQP11(-/-) mice displayed an altered electrophoretic mobility caused by impaired N-glycosylation processing, and density gradient centrifugation of kidney homogenate and in vivo protein biotinylation revealed impaired membrane trafficking of PC-1 in these mice. Finally, we showed that the Pkd1(+/-) background increased the severity of cystogenesis in AQP11(-/-) mouse kidneys, indicating that PC-1 is involved in the mechanism of cystogenesis in AQP11(-/-) mice. Additionally, the primary cilia of proximal tubules were elongated in AQP11(-/-) mice. Taken together, these data show that impaired glycosylation processing and aberrant membrane trafficking of PC-1 in AQP11(-/-) mice could be a key mechanism of cystogenesis in AQP11(-/-) mice.
- Published
- 2014
33. Diagnostic value of B-type natriuretic peptide for estimating left atrial size and its usefulness for predicting all-cause mortality and cardiovascular events among chronic haemodialysis patients
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Michio Kuwahara, Sei Sasaki, Junichi Ishigami, Yusuke Tsukamoto, and Soichiro Iimori
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medicine.medical_specialty ,Ejection fraction ,Receiver operating characteristic ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Hazard ratio ,General Medicine ,medicine.disease ,Confidence interval ,Nephrology ,Heart failure ,Internal medicine ,cardiovascular system ,Natriuretic peptide ,Cardiology ,Medicine ,cardiovascular diseases ,Risk factor ,business ,human activities ,hormones, hormone substitutes, and hormone antagonists ,Dialysis ,circulatory and respiratory physiology - Abstract
Aim Estimating fluid balance in haemodialysis patients is essential when determining dry weight, but limited methods are currently available. B-type natriuretic peptide (BNP) is a useful surrogate marker in patients with congestive heart failure (CHF), but whether its validity could be generalized to haemodialysis patients has not been studied well. Methods A total of 457 haemodialysis patients at a dialysis centre were analyzed. Determinants of BNP were assessed in connection with ultrasound cardiography (UCG) records, Kt/V, ultrafiltration rate (UFR), and demographic factors. All-cause death and cardiovascular (CV) events were recorded as the main outcome. Results Among the UCG records, left atrial diameter (LAD), left ventricular ejection fraction (LVEF), were determinants of log-transformed (ln) BNP; UFR, age and sex were also significant. There was a positive correlation between BNP and LAD (r = 0.285, P
- Published
- 2014
34. AQP2 in human urine is predominantly localized to exosomes with preserved water channel activities
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Yuko, Miyazawa, Saki, Mikami, Keiko, Yamamoto, Masaki, Sakai, Tatsuya, Saito, Tadashi, Yamamoto, Kenichi, Ishibashi, and Sei, Sasaki
- Subjects
Proteomics ,Aquaporin 2 ,Humans ,Water ,Exosomes ,Kidney ,Permeability - Abstract
AQP2 water channel is critical for urinary concentration in the kidney. Interestingly, AQP2 is abundantly excreted in the urine as extracellular vesicles (EVs), which is known to be a useful biomarker for water-balance disorders although the character of AQP2-enriched EVs is poorly understood including water channel function.Human urine EVs were obtained by a differential centrifugation method. AQP2-bearing EVs were isolated by immunoprecipitation with an AQP2-specific antibody, and the proteins in the EVs were analyzed by LC-MS/MS proteomic analysis. Osmotic water permeability (Pf) of the AQP2-rich EVs was measured by a stopped-flow method monitoring scattered light intensity in response to outwardly directed osmotic gradient.Sequential centrifugation of human urine showed that AQP2 was present predominantly (80%) in low-density EVs (160,000 g), whereas negligible amount in high-density EVs (17,000 g). Proteomic analysis of the AQP2-bearing EVs identified 137 proteins, mostly in the endosome pathway, including the components of ESCRT (endosomal sorting complex required transporter)-I, II, III. Pf value of the 160,000 g EVs was 4.75 ± 0.38 × 10Taken together, AQP2 is localized predominantly to urinary exosomes with preserved water channel activities.
- Published
- 2017
35. Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice
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Kiyoshi Isobe, Tatemitsu Rai, Naohiro Nomura, Naoki Takeda, Koichiro Susa, Takayasu Mori, Shinichi Uchida, Sei Sasaki, Yutaro Mori, Daiei Takahashi, Hidenori Nishida, Kenta Takeishi, Motoko Chiga, Yuichi Inoue, Moko Zeniya, and Eisei Sohara
- Subjects
medicine.medical_specialty ,Genotype ,Pseudohypoaldosteronism ,Genetic Vectors ,Mutant ,Gene Expression ,Mice, Transgenic ,Protein Serine-Threonine Kinases ,Kidney ,Sodium Channels ,Phosphorylation cascade ,Minor Histocompatibility Antigens ,Mice ,WNK Lysine-Deficient Protein Kinase 1 ,Internal medicine ,Gene Order ,Genetics ,medicine ,Animals ,Protein Interaction Domains and Motifs ,Potassium Channels, Inwardly Rectifying ,Molecular Biology ,Genetics (clinical) ,Adaptor Proteins, Signal Transducing ,biology ,urogenital system ,Kinase ,Microfilament Proteins ,Ubiquitination ,Epithelial Cells ,General Medicine ,medicine.disease ,WNK1 ,Molecular biology ,Ubiquitin ligase ,WNK4 ,Disease Models, Animal ,Phenotype ,Endocrinology ,Gene Targeting ,Mutation ,Proteolysis ,biology.protein ,Phosphorylation ,Protein Binding - Abstract
Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by salt-sensitive hypertension, hyperkalemia and metabolic acidosis, and genes encoding with-no-lysine kinase 1 (WNK1) and WNK4 kinases are known to be responsible. Recently, Kelch-like 3 (KLHL3) and Cullin3, components of KLHL3-Cullin3 E3 ligase, were newly identified as responsible for PHAII. We have reported that WNK4 is the substrate of KLHL3-Cullin3 E3 ligase-mediated ubiquitination. However, WNK1 and Na-Cl cotransporter (NCC) were also reported to be a substrate of KLHL3-Cullin3 E3 ligase by other groups. Therefore, it remains unclear which molecule is the target(s) of KLHL3. To investigate the pathogenesis of PHAII caused by KLHL3 mutation, we generated and analyzed KLHL3(R528H/+) knock-in mice. KLHL3(R528H/+) knock-in mice exhibited salt-sensitive hypertension, hyperkalemia and metabolic acidosis. Moreover, the phosphorylation of NCC was increased in the KLHL3(R528H/+) mouse kidney, indicating that the KLHL3(R528H/+) knock-in mouse is an ideal mouse model of PHAII. Interestingly, the protein expression of both WNK1 and WNK4 was significantly increased in the KLHL3(R528H/+) mouse kidney, confirming that increases in these WNK kinases activated the WNK-OSR1/SPAK-NCC phosphorylation cascade in KLHL3(R528H/+) knock-in mice. To examine whether mutant KLHL3 R528H can interact with WNK kinases, we measured the binding of TAMRA-labeled WNK1 and WNK4 peptides to full-length KLHL3 using fluorescence correlation spectroscopy, and found that neither WNK1 nor WNK4 bound to mutant KLHL3 R528H. Thus, we found that increased protein expression levels of WNK1 and WNK4 kinases cause PHAII by KLHL3 R528H mutation due to impaired KLHL3-Cullin3-mediated ubiquitination.
- Published
- 2014
36. PRIMARY AND SECONDARY GLOMERULONEPHRITIDES 1
- Author
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Masayuki Iyoda, Taihei Suzuki, Jung Eun Lee, Margherita Conrieri, Angel Sevillano, Katsuyuki Nagatoya, Shankar Prasad Nagaraju, Nicoletta Mezzina, Augusta Praça, A. Malesci, Bjørn Egil Vikse, Tajana Zeljkovic Vrkic, Fumihiko Sasai, Giuseppe Paolo Segoloni, Maki Shinzawa, Terumasa Hayashi, Yutaka Yamaguchi, Maria Elena Donadio, Inês Ferreira, Ioanna Labropoulou, Luca Vergano, Yoshikuni Nagayama, Manuel A Podestà, Guida Meneses, Takayuki Kuragano, Gisele V. Fernandes, Manohar Bairy, Yasuyuki Nagasawa, Ayse Serra Artan, Vedran Premuzic, Barbara Trezzi, Carla Guidi, Manuel Pestana, Makoto Watanabe, Donatella Vizza, Francisco Remédio, Rune Bjørneklett, Niranjan Ambekar, Evangelina Mérida, Narayan Prasad, Ana Cristina Matos, George Toulkeridis, In Mi Han, Enrique Morales, Mohit Kumar Rai, Federica Chiale, Kenichi Sumida, Ann Merethe Vågane, E. Mariz, Adrian Zugravu, Andreas Kronbichler, Michael A. Rudnicki, Praga Manuel, Maria Skoularopoulou, Maria Paola Puccinelli, Mustafa Güllülü, Helena Viana, Loredana Colla, Vasudeva Guddattu, Sung-Bae Park, Sung Jin Moon, Eduardo Gutiérrez, Hirokatsu Atsumi, Junichi Hoshino, Rajeevalochana Parthasarathy, Nimet Aktas, Renzo Bonofilgio, Carla Henriques, Ana Huerta, Jelena Kos, David Cucchiari, Gener Ismail, Renato Alberto Sinico, Anna Varberg Reisæter, Hideki Yamaya, Iuliana Andreiana, Atsushi Yamauchi, Bernardo Faria, Francesca Maria Bosetti, Noriko Hayami, Vincenzo Cantaluppi, Yoshitaka Isaka, Swapnil Karnik, Aydin Turkmen, Alexei Smirnov, Ljiljana Fodor, Jinhyuk Paek, Alberto Boido, Shinichi Uchida, Abdulmecit Yildiz, Takanori Shibata, Sei Sasaki, Xiao-Yan Wei, Ravindra Prabhu, Tiziana Stellato, Roser Torra, Eunah Hwang, Kazuyuki Tasaki, Luigi Biancone, Gutierrez-Solis Elena, Clarissa J. B. Carvalho, Gabriel Mircescu, Ana Teresa Nunes, Elisabet Ars, Tomokazu Okado, Hui Wang, Vanja Ivković, Tushar Anil Dighe, Katsuhito Ihara, Norifumi Hayashi, Roxana Jurubita, Aysegul Oruc, Yasar Caliskan, Mehmet Sukru Sever, Atul Sajgure, Aikaterini Papagianni, Katarzyna Koscielska-Kasprzak, Francesca Leone, Mario Laganović, Archana Buch, Daisuke Komukai, Carina Ferreira, Olga Galkina, Marian Klinger, Sandra Karanović, Manuela Bianciotto, Srinivas Kosuru, Maria Céu Santos, Maurizio Gallieni, Manuel Praga, Yuan-Qing Tian, Ken Iseri, Peter Påhlsson, Kenmei Takaichi, Vikas Agarwal, Manuel Burdese, Aritoshi Kida, Giulio Mengozzi, Giovanni Camussi, Yasutaka Yamamoto, Tomohiro Saito, Seiichi Matsuo, Enyu Imai, Yuki Shindo-Hirai, Edite Pereira, Nida Oztop, Gert Mayer, Tatemitsu Rai, Rosanna Coppo, Hiroshi Okuyama, Dong Ho Shin, Soichiro Iimori, Danilo Lofaro, Hiroki Adachi, Yasemin Ozluk, Maria Alina Gomes de Mattos Cavalcante, Michael C. Carlsson, Bulent Gul, Abhay Sadre, Shunsuke Goto, Vasilii Sipovskii, Kei Fukami, Hiroki Nishiwaki, Tatsuya Suwabe, Daniela Finocchietti, Yuki Matsui, Takshi Nakanishi, Ashwini Sharma, Teresa Papalia, Marijana Cˇorić, Marco D'Amico, Caro-Espada Paula Jara, Francesco Mollica, Licia Peruzzi, Yukihiro Wada, Roberta Camilla, Agata Mollica, E. O. Bogdanova, Raluca Bobeica, Cai-Li Wang, Eugen Mandache, Francesco Reggiani, Joaquim Calado, Li Lv, Elena Saganova, Fernanda Carvalho, Halil Yazici, Yan-Hui Zhang, Elisa Loiacono, Christos Bantis, Teresa Cavero, Salvatore Badalamenti, Hakon Leffler, Sigrid Lundberg, Tarun Jeloka, Ligia Petrescu, Luca Besso, Alline S. A. Oliveira, Stratis Kasimatis, Thomas Knoop, Davide Medica, Germana Daidola, E. Hernandez, Mana Yahiro, Rojas-Rivera Jorge Enrique, João M. Frazão, Kouki Mise, Toshiaki Suzuki, Yoshihiro Kuno, Atul Mulay, Jun Ito, Katarzyna Gniewek, George Efstratiadis, Marijana Ćorić, Jara Caro, Maria Stangou, Aysun Aksoy, Fernando Nolasco, Katarzyna Jakuszko, Paolo Gigliotti, Tae Hyun Yoo, Takeshi Hasegawa, Hideki Fujii, Ricardo Neto, Simona Stancu, Susana Sampaio, Camila Barbosa L Oliveira, Sindhura Lakshmi Koulmane Laxminarayana, Alaattin Yildiz, Shigeo Hara, Kei Matsumoto, Ludmila Taran, Nikoleta Maria Kouri, Shinichi Nishi, Andreea Avram, Zivka Dika, Nobuharu Kaneshima, Charan Bhadrappa Bale, Gian Marco Ghiggeri, Ashio Yoshimura, Lei Nan, Rachele Gallo, Keiji Fujimoto, Alessandro Amore, Mårten Segelmark, Luís H. B. C. Sette, Francesca Brunini, Bojan Jelaković, Lucila Maria Valente, Ryohei Yamamoto, Andreea Andronesi, Julia Kerschbaum, Inna Lastauka, Mohamed R. Daha, Akhilesh Jaiswal, Ni-Ya Jia, Jayraj Korpe, Shinichi Akiyama, Domenico Santoro, Marc A. Seelen, Ebru Acikgoz, Shoichi Maruyama, Anna Perri, Hitoshi Yokoyama, Magdalena Krajewska, Brijesh Yadav, Hyungjong Kim, Irina Zubina, Tatsuya Shoji, Yoshifumi Ubara, Claudio Angelini, Margareta Fištrek Prlić, Ian Proletov, Kentaro Nakai, Isin Kilicaslan, Antonella Radice, Prachi Kate, Sayuri Hamahata, Jose Antonio Moreno, and Marijana Zivko
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Transplantation ,medicine.medical_specialty ,Pediatrics ,Primary (chemistry) ,Nephrology ,business.industry ,Alternative medicine ,medicine ,business ,Intensive care medicine - Published
- 2014
37. Decreased mobility after starting dialysis is an independent risk factor for short-term mortality after initiation of dialysis
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Naoto Inaba, Makoto Aoyagi, Hiroaki Kikuchi, Sei Sasaki, Eiichiro Kanda, Chisato Yamamura, Suguru Hirasawa, Yohei Arai, Teiichi Tamura, Shota Aki, and Hiroyuki Tanaka
- Subjects
medicine.medical_specialty ,Proportional hazards model ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Short term mortality ,Retrospective cohort study ,General Medicine ,Decreased mobility ,Confidence interval ,Surgery ,Nephrology ,Internal medicine ,medicine ,Risk factor ,business ,Dialysis - Abstract
Aim Impaired mobility at the onset of dialysis is considered one of the most important risk factors for short-term mortality after initiation of dialysis in elderly patients. However, whether a decline in mobility after starting dialysis also affects mortality is unclear. Methods A total of 202 patients (age, >75 years; mean, 80.4 ± 4.3) were enrolled in this retrospective cohort study in Yokosuka, Japan. They were divided into three subgroups by mobility: independent mobility at onset of dialysis and preservation of mobility after starting dialysis (group 1, n = 104); independent mobility at onset of dialysis and decline in mobility after starting dialysis (group 2, n = 48); and impaired mobility at onset of dialysis (group 3, n = 50). They were followed for 6 months after starting dialysis. A Cox proportional hazards model was used to evaluate the association between mobility and mortality. Results A total of 24.8% of patients had impaired mobility at the start of dialysis, and 68.9% declined in mobility after starting dialysis. In multivariate Cox proportional hazards analysis, the adjusted hazard ratios of groups 2 and 3 compared with group 1 were 3.80 (95% confidence interval, 1.02–14.10) and 4.94 (95% confidence interval, 1.42–17.10), respectively. Conclusion Not only impaired mobility at the start of dialysis but also a decline in mobility after starting dialysis is associated with short-term mortality after initiation of dialysis.
- Published
- 2014
38. Regulation of with‐no‐lysine kinase signaling by Kelch‐like proteins
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Sei Sasaki, Eisei Sohara, Tatemitsu Rai, and Shinichi Uchida
- Subjects
Pseudohypoaldosteronism ,Kinases ,Review ,Protein Serine-Threonine Kinases ,Biology ,Kidney ,Minor Histocompatibility Antigens ,WNK Lysine-Deficient Protein Kinase 1 ,Ubiquitin ,medicine ,Animals ,Humans ,Gene ,Adaptor Proteins, Signal Transducing ,Genetics ,Membrane transport ,Protein-Serine-Threonine Kinases ,urogenital system ,Kinase ,Cullin Proteins ,Microfilament Proteins ,Intracellular Signaling Peptides and Proteins ,Cell Biology ,General Medicine ,medicine.disease ,Hypertension ,biology.protein ,Signal transduction ,Carrier Proteins ,Signal Transduction - Abstract
In 2001, with-no-lysine (WNK) kinases were identified as the genes responsible for the human hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). It took a further 6 years to clarify that WNK kinases participate in a signaling cascade with oxidative stress-responsive gene 1 (OSR1), Ste20-related proline-alanine-rich kinase (SPAK), and thiazide-sensitive NaCl cotransporter (NCC) in the kidney and the constitutive activation of this signaling cascade is the molecular basis of PHAII. Since this discovery, the WNK-OSR1/SPAK-NCC signaling cascade has been shown to be involved not only in PHAII but also in the regulation of blood pressure under normal and pathogenic conditions, such as hyperinsulinemia. However, the molecular mechanisms of WNK kinase regulation by dietary and hormonal factors and by PHAII-causing mutations remain poorly understood. In 2012, two additional genes responsible for PHAII, Kelch-like 3 (KLHL3) and Cullin3, were identified. At the time of their discovery, the molecular mechanisms underlying the interaction between these genes and their involvement in PHAII were unknown. Here we review the pathophysiological roles of the WNK signaling cascade clarified to date and introduce a new mechanism of WNK kinase regulation by KLHL3 and Cullin3, which provides insight on previously unknown mechanisms of WNK kinase regulation.
- Published
- 2014
39. 5. Channels, Transporters, and Kidney Diseases
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Sei Sasaki
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Kidney ,Pathology ,medicine.medical_specialty ,medicine.anatomical_structure ,Continuing medical education ,business.industry ,Family medicine ,Medicine ,General Medicine ,Session (computer science) ,business - Published
- 2014
40. 4. Homeostatic Regulation of Body Fluid by Kidney and Its Disturbances
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Sei Sasaki
- Subjects
Body fluid ,Kidney ,medicine.medical_specialty ,medicine.anatomical_structure ,business.industry ,MEDLINE ,medicine ,General Medicine ,business ,Intensive care medicine ,Homeostasis - Published
- 2014
41. Wnt5a induces renal AQP2 expression by activating calcineurin signalling pathway
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Eriko Kikuchi, Tetsuji Morimoto, Naofumi Yui, Naohiro Nomura, Takayasu Mori, Fumiaki Ando, Eisei Sohara, Daiei Takahashi, Alain Vandewalle, Tatemitsu Rai, Shinichi Uchida, Yoshiaki Kondo, and Sei Sasaki
- Subjects
Male ,0301 basic medicine ,Vasopressin ,Dishevelled Proteins ,General Physics and Astronomy ,Diabetes Insipidus, Nephrogenic ,Kidney ,urologic and male genital diseases ,Phosphoserine ,Cyclic AMP ,Phosphorylation ,beta Catenin ,Arachidonic Acid ,Multidisciplinary ,Chemistry ,Calcineurin ,Hedgehog signaling pathway ,Cell biology ,Protein Transport ,Aquaporin 2 ,Signal Transduction ,Science ,Models, Biological ,Article ,Permeability ,Wnt-5a Protein ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,medicine ,Animals ,Calcium Signaling ,RNA, Messenger ,urogenital system ,Activator (genetics) ,Osmolar Concentration ,Water ,Kidney metabolism ,General Chemistry ,Apical membrane ,Nephrogenic diabetes insipidus ,medicine.disease ,Cyclic AMP-Dependent Protein Kinases ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,Calcium - Abstract
Heritable nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentration mechanisms in the kidney, which are mainly caused by loss-of-function mutations in the vasopressin type 2 receptor. For the treatment of heritable NDI, novel strategies that bypass the defective vasopressin type 2 receptor are required to activate the aquaporin-2 (AQP2) water channel. Here we show that Wnt5a regulates AQP2 protein expression, phosphorylation and trafficking, suggesting that Wnt5a is an endogenous ligand that can regulate AQP2 without the activation of the classic vasopressin/cAMP signalling pathway. Wnt5a successfully increases the apical membrane localization of AQP2 and urine osmolality in an NDI mouse model. We also demonstrate that calcineurin is a key regulator of Wnt5a-induced AQP2 activation without affecting intracellular cAMP level and PKA activity. The importance of calcineurin is further confirmed with its activator, arachidonic acid, which shows vasopressin-like effects underlining that calcineurin activators may be potential therapeutic targets for heritable NDI., The water channel AQP2 mediates the concentration of urine in the kidney. Here Ando et al. show that Wnt5 promotes collecting duct permeability by regulating AQP2 expression and localization through activation of the calmodulin/calcineurin signalling pathway.
- Published
- 2016
42. Low white blood cell count is independently associated with chronic kidney disease progression in the elderly: the CKD-ROUTE study
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Tomokazu Okado, Tatemitsu Rai, Eisei Sohara, Eiichiro Kanda, Sei Sasaki, Yumi Noda, Soichiro Iimori, Shinichi Uchida, Yohei Arai, and Shotaro Naito
- Subjects
0301 basic medicine ,Nephrology ,Male ,medicine.medical_specialty ,Time Factors ,Physiology ,030232 urology & nephrology ,Renal function ,Kaplan-Meier Estimate ,Kidney ,End stage renal disease ,03 medical and health sciences ,Leukocyte Count ,0302 clinical medicine ,Japan ,Predictive Value of Tests ,Risk Factors ,Physiology (medical) ,Internal medicine ,White blood cell ,medicine ,Leukocytes ,Humans ,Prospective Studies ,Renal Insufficiency, Chronic ,Prospective cohort study ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,business.industry ,Hazard ratio ,Age Factors ,Middle Aged ,medicine.disease ,Prognosis ,Confidence interval ,030104 developmental biology ,medicine.anatomical_structure ,Logistic Models ,Disease Progression ,Kidney Failure, Chronic ,Female ,business ,Kidney disease ,Glomerular Filtration Rate - Abstract
Elevated white blood cell (WBC) count is a well-known predictor of chronic kidney disease (CKD) progression. However, elderly patients commonly fail to develop a high WBC count in response to several diseased states and may instead present a low WBC count. Therefore, we hypothesized that low WBC count, in addition to high WBC count, is associated with CKD progression in the elderly. We conducted a prospective cohort study using 3-year follow-up data from the CKD Research of Outcomes in Treatment and Epidemiology study. In the present study, participants aged over 60 years with pre-dialysis CKD stages G2–G5 were eligible. Patients were stratified into three groups according to WBC count using tertiles (T). The primary outcome was a composite of end-stage renal disease and a 50% reduction in estimated glomerular filtration rate. Data were analyzed using Cox proportional hazard models with adjustments for covariates. We enrolled 697 patients (males, 69%). The median WBC count was 6100 cells/µl (T1
- Published
- 2016
43. Effects of three kinds of erythropoiesis-stimulating agents on renal anemia in Japanese non-dialysis chronic kidney disease patients
- Author
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Satomi Shikuma, Yoshihiro Mori, Syoko Hasumi, Shintaro Mandai, Tomomi Tanaka, Wataru Akita, Sei Sasaki, and Michio Kuwahara
- Subjects
Male ,Nephrology ,medicine.medical_specialty ,Darbepoetin alfa ,Physiology ,Anemia ,urologic and male genital diseases ,Cohort Studies ,Japan ,hemic and lymphatic diseases ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Renal Insufficiency, Chronic ,Erythropoietin ,Aged ,Aged, 80 and over ,Epoetin beta ,business.industry ,Epoetin alfa ,Middle Aged ,medicine.disease ,Recombinant Proteins ,female genital diseases and pregnancy complications ,Epoetin Alfa ,Hematinics ,Erythropoiesis ,Female ,business ,medicine.drug ,Cohort study ,Kidney disease - Abstract
Erythropoiesis-stimulating agents (ESAs) are standard therapy for chronic kidney disease (CKD) patients with renal anemia. However, few studies have compared the effects of different ESAs on anemia in identical pre-dialysis CKD patients.Seventy-nine patients who switched from epoetin beta to darbepoetin alfa (Group 1), and 82 patients who switched from darbepoetin alfa to epoetin beta pegol (Group 2) were enrolled in this study. Clinical and laboratory parameters were assessed for 6 months before and after switching ESAs. The prevalence of adverse events, the dose conversion ratio of ESAs, and the frequency of ESA administration were also analyzed.Analysis of variance showed that switching ESAs did not significantly change hemoglobin levels for the study duration in both groups (mean hemoglobin 10.3-10.5 g/dL in Group 1 and 10.4-10.7 g/dL in Group 2). Estimated glomerular filtration rate, blood pressure, transferrin saturation, ferritin, and albumin remained constant in both groups. The prevalence of adverse effects was quite low (0-3.8 %) during both 6-month study periods. The mean dose conversion ratio for epoetin beta:darbepoetin alfa was 163.7 units:1 μg and for darbepoetin alfa:epoetin beta pegol was 1.08 μg:1 μg. The intervals of ESA administration significantly differed (epoetin beta pegoldarbepoetin alfaepoetin beta).Epoetin beta, darbepoetin alfa, and epoetin beta pegol are effective and well-tolerated agents for managing anemia in Japanese pre-dialysis CKD patients. The intervals of ESA administration to maintain a patient's target hemoglobin were longer in the order of epoetin beta pegoldarbepoetin alfaepoetin beta.
- Published
- 2013
44. Functional coupling of chloride–proton exchanger ClC-5 to gastric H+,K+-ATPase
- Author
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Kazuhiro Tsukada, Yuji Takahashi, Kyosuke Fujita, Sei Sasaki, Hideki Sakai, Koji Manabe, Shinichi Uchida, Takahiro Shimizu, Takuto Fujii, Hisato Sakamoto, Akira Ikari, Ichiro Naito, Yoshiaki Tabuchi, and Taiga Higuchi
- Subjects
Hydrogen potassium ATPase ,QH301-705.5 ,Science ,ATPase ,Mutant ,ClC-5 ,General Biochemistry, Genetics and Molecular Biology ,Parietal cell ,medicine ,H+,K+-ATPase ,Secretion ,Biology (General) ,biology ,urogenital system ,Vesicle ,Gastric acid ,Molecular biology ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,General Agricultural and Biological Sciences ,Tubulovesicle ,Intracellular ,Research Article - Abstract
Summary It has been reported that chloride–proton exchanger ClC-5 and vacuolar-type H+-ATPase are essential for endosomal acidification in the renal proximal cells. Here, we found that ClC-5 is expressed in the gastric parietal cells which secrete actively hydrochloric acid at the luminal region of the gland, and that it is partially localized in the intracellular tubulovesicles in which gastric H+,K+-ATPase is abundantly expressed. ClC-5 was co-immunoprecipitated with H+,K+-ATPase in the lysate of tubulovesicles. The ATP-dependent uptake of 36Cl− into the vesicles was abolished by 2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile (SCH28080), an inhibitor of H+,K+-ATPase, suggesting functional expression of ClC-5. In the tetracycline-regulated expression system of ClC-5 in the HEK293 cells stably expressing gastric H+,K+-ATPase, ClC-5 was co-immunoprecipitated with H+,K+-ATPase, but not with endogenous Na+,K+-ATPase. The SCH28080-sensitive 36Cl− transporting activity was observed in the ClC-5-expressing cells, but not in the ClC-5-non-expressing cells. The mutant (E211A-ClC-5), which has no H+ transport activity, did not show the SCH28080-sensitive 36Cl− transport. On the other hand, both ClC-5 and its mutant (E211A) significantly increased the activity of H+,K+-ATPase. Our results suggest that ClC-5 and H+,K+-ATPase are functionally associated and that they may contribute to gastric acid secretion.
- Published
- 2013
45. Development of enzyme-linked immunosorbent assays for urinary thiazide-sensitive Na-Cl cotransporter measurement
- Author
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Shinichi Uchida, Sei Sasaki, Kiyoshi Isobe, Takako Asano, Naonori Kumagai, Takayasu Mori, Shigeaki Nonoyama, Eisei Sohara, Tetsuji Morimoto, Hiroyuki Kawaguchi, Fumiaki Kamada, Tatemitsu Rai, and Matsuhiko Hayashi
- Subjects
Male ,medicine.medical_specialty ,Physiology ,Pseudohypoaldosteronism ,Sodium Chloride Symporter Inhibitors ,Urinary system ,Enzyme-Linked Immunosorbent Assay ,Urine ,Exosomes ,Exosome ,Mice ,Internal medicine ,parasitic diseases ,medicine ,Animals ,Humans ,Solute Carrier Family 12, Member 3 ,Clinical significance ,Phosphorylation ,Aged ,chemistry.chemical_classification ,Kidney ,urogenital system ,Middle Aged ,Gitelman syndrome ,medicine.disease ,Enzyme ,medicine.anatomical_structure ,Endocrinology ,chemistry ,embryonic structures ,Female ,Cotransporter ,Gitelman Syndrome - Abstract
The Na-Cl cotransporter (NCC) in the distal convoluted tubules in kidney is known to be excreted in urine. However, its clinical significance has not been established because of the lack of quantitative data on urinary NCC. We developed highly sensitive enzyme-linked immunosorbent assays (ELISAs) for urinary total NCC (tNCC) and its active form, phosphorylated NCC (pNCC). We first measured the excretion of tNCC and pT55-NCC in urinary exosomes in pseudohypoaldosteronism type II (PHAII) patients since PHAII is caused by NCC activation. Highly increased excretion of tNCC and pNCC was observed in PHAII patients. In contrast, the levels of tNCC and pNCC in the urine of patients with Gitelman's syndrome were not detectable or very low, indicating that both assays could specifically detect the changes in urinary NCC excretion caused by the changes of NCC activity in the kidney. Then, to test whether these assays could be feasible for a more general patient population, we measured tNCC and pNCC in the urine of outpatients with different clinical backgrounds. Although urinary protein levels >30 mg/dl interfered with our ELISA, we could measure urinary pNCC in all patients without proteinuria. Thus we established highly sensitive and quantitative assays for urinary NCC, which could be valuable tools for estimating NCC activity in vivo.
- Published
- 2013
46. Dietary Salt Intake Regulates WNK3–SPAK–NKCC1 Phosphorylation Cascade in Mouse Aorta Through Angiotensin II
- Author
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Shih-Hua Lin, Koichiro Susa, Daiei Takahashi, Eisei Sohara, Katsuyuki Oi, Sung-Sen Yang, Sei Sasaki, Motoko Chiga, Tatemitsu Rai, Takayasu Mori, Takahiro Iwamoto, Satomi Kita, Moko Zeniya, and Shinichi Uchida
- Subjects
medicine.medical_specialty ,Angiotensin receptor ,Vascular smooth muscle ,Tetrazoles ,Blood Pressure ,Protein Serine-Threonine Kinases ,Biology ,Phosphorylation cascade ,Mice ,Internal medicine ,Renin–angiotensin system ,Internal Medicine ,medicine ,Animals ,Solute Carrier Family 12, Member 2 ,Phosphorylation ,Mesenteric arteries ,Aorta ,Mice, Knockout ,Angiotensin II receptor type 1 ,Angiotensin II ,Sodium, Dietary ,Valine ,Mesenteric Arteries ,Endocrinology ,medicine.anatomical_structure ,Valsartan ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug - Abstract
Na–K–Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction. Recently, the with-no-lysine kinase (WNK)–STE20/SPS1-related proline/alanine-rich kinase (SPAK)–NKCC1 phosphorylation cascade in vascular smooth muscle cells was found to be important in the regulation of vascular tone. In this study, we investigated whether the WNK–SPAK–NKCC1 cascade in mouse aortic tissue is regulated by dietary salt intake and the mechanisms responsible. Phosphorylation of SPAK and NKCC1 was significantly reduced in the aorta in high-salt–fed mice and was increased in the aorta in low-salt–fed mice, indicating that the WNK–SPAK–NKCC1 phosphorylation cascade in the aorta was indeed regulated by dietary salt intake. Acute and chronic angiotensin II infusion increased phosphorylation of SPAK and NKCC1 in the mouse aorta. In addition, valsartan, an antagonist of angiotensin II type 1 receptor, inhibited low-salt diet–induced phosphorylation of SPAK and NKCC1, demonstrating that angiotensin II activates the WNK–SPAK–NKCC1 phosphorylation cascade through the angiotensin II type 1 receptor. However, a low-salt diet and angiotensin II together did not increase phosphorylation of SPAK and NKCC1 in the aorta in WNK3 knockout mice, indicating that activation of the WNK–SPAK–NKCC1 phosphorylation cascade induced by a low-salt diet and angiotensin II is dependent on WNK3. Indeed, angiotensin II–induced increases in blood pressure were diminished in WNK3 knockout mice. In addition, decreased response to angiotensin II in the mesenteric arteries was observed in WNK3 knockout mice. Our data also clarified a novel mechanism for regulation of vascular tonus by angiotensin II. Inhibition of this cascade could, therefore, be a novel therapeutic target in hypertension.
- Published
- 2013
47. Successful Treatment of Mycobacterium chelonae Peritoneal Dialysis-Related Infection by a Combination Regimen Including Local Thermal Therapy
- Author
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Eisei Sohara, Tatemitu Rai, Hidenori Nishida, Shinichi Uchida, Soichiro Iimori, Naofumi Yui, Tomokazu Okado, and Sei Sasaki
- Subjects
Hyperthermia ,medicine.medical_specialty ,biology ,business.industry ,medicine.medical_treatment ,MEDLINE ,Mycobacterium chelonae ,Thermal therapy ,General Medicine ,biology.organism_classification ,medicine.disease ,Peritoneal dialysis ,Surgery ,Regimen ,Pharmacotherapy ,Nephrology ,Correspondence ,medicine ,Combined Modality Therapy ,business - Published
- 2015
48. Rate of Ankle-Brachial Index Decline Predicts Cardiovascular Mortality in Hemodialysis Patients
- Author
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Sei Sasaki, Tomomi Tanaka, Wataru Akita, Michio Kuwahara, Syoko Hasumi, Yoshihiro Mori, Satomi Shikuma, and Shintaro Mandai
- Subjects
medicine.medical_specialty ,Proportional hazards model ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Hematology ,Disease ,medicine.disease ,Surgery ,body regions ,medicine.anatomical_structure ,Nephrology ,Internal medicine ,medicine ,Cardiology ,cardiovascular diseases ,Hemodialysis ,Ankle ,Risk factor ,business ,Pulse wave velocity ,Kidney disease - Abstract
Chronic kidney disease is a risk factor for cardiovascular mortality and morbidity of cardiovascular events (CVEs). We obtained baseline data regarding blood biochemistry, ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV) and echocardiographic parameters from 300 patients on hemodialysis in 2005. We also measured ABI and baPWV annually from June 2005 until June 2012 and calculated rates of changes in ABI and baPWV to identify factors associated with CVEs. Seventy-three patients died of cardiovascular disease and 199 CVEs occurred in 164 patients during the study period. Cardiac, cerebrovascular and peripheral artery disease (PAD) events occurred in 124, 43 and 32 patients, respectively, and 30 patients had more than two types of CVEs. Analysis using the Cox proportional hazards model showed that a higher rate of decline in ABI (hazard ratio [HR], 4.034; P < 0.001) was the most significant risk factor for decreased patient survival. Multivariate Cox analysis revealed that a higher rate of ABI decline (HR, 2.342; P < 0.001) was a significant risk factor for cardiac events, and that a lower baseline ABI was a risk factor for cerebrovascular (HR, 0.793; P = 0.03) and PAD (HR, 0.595; P < 0.0001) events. Our findings suggested that the rate of a decline in ABI and the baseline ABI value are potent correlation factors for survival and CVE morbidity among patients on hemodialysis in Japan.
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- 2013
49. Epidemiology - cardiovascular outcomes
- Author
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Eric Verbeken, Yumi Noda, Paula Specht, Angels Betriu, Ahad A. Abdalla, Bogusław Okopień, Isabelle Jaussent, Magdalena Olszanecka-Glinianowicz, MariaJose Soler, Krzysztof Labuzek, Tuan Ismail, Soo Bong Lee, Mai Sugahara, Izumi Sugimoto, Jung Eun Lee, Mohammad Ibrahim Anan, Olle Melander, Naobumi Mise, Yasuhisa Sakurai, Ailish Hannigan, Kazuko Suzuki, Cornelius J. Cronin, Isao Kubota, Harin Rhee, Nihil Chitalia, Tomokazu Okado, Amir E.L. Okely, Ludomir Stefańczyk, Masanori Emoto, Esam Lotfy Harash, Francesca Mallamaci, Magdalena Kaczmarska, Markus Ketteler, Célia Brugueirolle, Rafał Ficek, Sei Sasaki, Ghislain Opdenakker, Toshihide Naganuma, Göran Berglund, Erik Fjellstedt, Tetsuo Shoji, Jürgen Floege, Kristien Daenen, Sung Kyu Ha, Mikio Okamura, Hoon Young Choi, Hélène Leray-Moragues, Anne-Marie Dupuy, Michał Nowicki, Kenichi Ishizawa, Anna Faura, Marc Hoylaerts, Sol Otero, Tatsuya Nakatani, Il Young Kim, Astrid Weiland, Masaaki Inaba, Daniela Leonardis, Piotr Grzelak, Malaka Yehya Fouad, Inge Fourneau, Austin G. Stack, Wael Fouad Nassar, Jerzy Chudek, Byeong Yun Yang, Ilona Kurnatowska, Rika Miura, In Hye Hwang, Elvira Fernández, David Goldsmith, Jean-Paul Cristol, Hyeong Cheon Park, Bert Bammens, Julio Pascual, Hideaki Shima, Mohammad Hany Hafez, Silvia Collado, Dong Won Lee, Frances Boa, Andrzej Wiecek, Anders Christensson, Min Ji Shin, Seung Kyo Park, Kosuke Kudo, Katarzyna Wyskida, Ayako Tsuchiya, Sergi Mojal, Liam F. Casserly, Ihm Soo Kwak, Laura Tooth, Tatemitsu Rai, Eva Rodríguez, Leila Chenine, Bernard Canaud, Soichiro Iimori, Lisa Uchida, Davide Bolignano, Anna Masajtis-Zagajewska, Rocco Tripepi, Mahmoud E.L. Temraz, Marion Morena, Takafumi Kanemitsu, Muriel Giansily-Blaizot, Juan C. Kaski, Katsuhito Mori, Eiji Ishimura, Maria Andersson-Ohlsson, Nagaaki Kotera, Shinichi Uchida, Kazunobu Ichikawa, Eun Young Seong, Shinya Nakatani, Masatomo Chikamori, Kyung Nam Lee, Shotaro Naito, Tsuneo Konta, Agnieszka Zak-Gołab, Masafumi Kobayashi, Clara Barrios, Mostafa Abdelaziz Mostafa, Debasish Banerjee, Vincent Brandenburg, Hoang T. Nguyen, Tomoko Honda, Jean-François Schved, Yaser Mohammad Hendi, Kornel Pośpiech, and Carmine Zoccali
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Transplantation ,medicine.medical_specialty ,Nephrology ,business.industry ,Epidemiology ,Medicine ,business ,Intensive care medicine ,Cardiovascular outcomes - Published
- 2013
50. Immunolocalization and translocation of aquaporin-5 water channel in sweat glands
- Author
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Eisei Sohara, Sei Sasaki, Risako Inoue, Shinichi Uchida, Hiroo Yokozeki, Takahiro Satoh, and Tatemitsu Rai
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Cytoplasm ,medicine.medical_specialty ,Aquaporin ,Sweating ,Chromosomal translocation ,Dermatology ,Biology ,Transfection ,Bone canaliculus ,Biochemistry ,Madin Darby Canine Kidney Cells ,Mice ,Dogs ,Body Water ,Chloride Channels ,Internal medicine ,Sweat gland ,medicine ,Animals ,Humans ,Secretion ,Molecular Biology ,Anoctamin-1 ,Calcium metabolism ,integumentary system ,Cell Membrane ,Cell Polarity ,Immunohistochemistry ,Aquaporin 5 ,Sweat Glands ,Cell biology ,Mice, Inbred C57BL ,Protein Transport ,Membrane ,Endocrinology ,medicine.anatomical_structure ,Calcium ,Intracellular ,Signal Transduction - Abstract
Background Aquaporin-5 (AQP5) is a member of the water channel protein family. Although AQP5 was shown to be present in sweat glands, the presence or absence of regulated intracellular translocation of AQP5 in sweat glands remained to be determined. Objective We investigated whether AQP5 in sweat glands translocated during sweating, and also sought to determine the intracellular signal that triggers this translocation. Methods Immunofluorescent analyses of AQP5 in mouse and human sweat glands were performed. Madin-Darby Canine kidney (MDCK) cell lines stably expressing human AQP5 were generated, and the regulated translocation of AQP5 in the polarized cells was assessed by immunofluorescent analysis and biotinylation assays. Results AQP5 showed rapid translocation to the apical membranes during sweating. In human eccrine sweat glands, immunoreactive AQP5 was detected in the apical membranes and the intercellular canaliculi of secretory coils, and in the basolateral membranes of the clear cells. Treatment of human AQP5-expressing MDCK cells with calcium ionophore A23187 resulted in a twofold increase of AQP5 in the apical membranes within 5 min. Conclusion The regulated AQP5 translocation may contribute to sweat secretion by increasing the water permeability of apical plasma membranes of sweat glands.
- Published
- 2013
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