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BackgroundWe investigated the association between ambulatory blood pressure (BP) and the risk of home hypertension in a normotensive population and whether considering ambulatory BP improves the 10-year prediction model for home hypertension risk, which was developed in the previous Ohasama Study.MethodsIn this prospective study, we followed up with 410 participants (83.2% women; age, 53.6 years) without a home and ambulatory hypertension in the general population of Ohasama, Japan. The Cox model was used to assess the hazard ratios (HRs) for home hypertension (home BP ≥ 135/≥85 mmHg or the initiation of antihypertensive treatment) and model improvement.ResultsDuring a mean 14.2-year follow-up, 225 home hypertension incidences occurred. The HR (95% confidence interval) for home hypertension incidence per 1-SD higher (=6.76 mmHg) 24-hour systolic BP (SBP) was 1.59 (1.33 to 1.90), after adjustments for possible confounding factors, including baseline home SBP. Harrell’s C-statistics increased from 0.72 to 0.73 (P = 0.11) when 24-hour SBP was added to the basic 10-year home hypertension prediction model, which includes sex, age, body mass index, smoking status, office SBP, and baseline home SBP. Continuous net reclassification improvement (0.53, P ConclusionsA total of 24-hour SBP could be an independent predictor of future home hypertension. Home BP and 24-hour BP can longitudinally influence each other in the long term.

(Pro)renin receptor [(P)RR] is related to both the renin-angiotensin system and V-ATPase with various functions including stimulation of cell proliferation. (P)RR is implicated in the pathophysiology of diabetes mellitus and cancer. Hyperinsulinemia is observed in obesity-related breast cancer. However, the relationship between (P)RR and insulin has not been clarified. We have therefore studied the effect of insulin on (P)RR expression, cell viability and AKT phosphorylation under the conditions with and without (P)RR knockdown. Effects of insulin were studied in a human breast cancer cell line, MCF-7. Cell proliferation assay was performed by WST-8 assay. (P)RR expression was suppressed by (P)RR-specific siRNAs. The treated cells were analysed by western blotting and reverse transcriptase-quantitative polymerase chain reaction analysis. Insulin stimulated proliferation of MCF-7 cells and increased (P)RR protein expression, but not (P)RR mRNA levels. Moreover, autophagy flux was suppressed by insulin. Suppression of (P)RR expression reduced cell number of MCF-7 cells and AKT phosphorylation significantly in both the presence and the absence of insulin, indicating that (P)RR is important for cell viability and AKT phosphorylation. In conclusion, insulin upregulates the level of (P)RR protein, which is important for cell viability, proliferation, AKT phosphorylation and autophagy in breast cancer cells.

Increased central venous pressure in congestive heart failure is responsible for renal dysfunction, which is mediated by renal venous congestion. Pericyte detachment from capillaries after renal congestion might trigger renal fibrogenesis via pericyte-myofibroblast transition (PMT). Platelet-derived growth factor receptors (PDGFRs), which are PMT indicators, were upregulated in our recently established renal congestion model. This study was designed to determine whether inhibition of the PDGFR pathway could suppress tubulointerstitial injury after renal congestion.The inferior vena cava between the renal veins was ligated in male Sprague-Dawley rats, inducing congestion only in the left kidney. Imatinib mesylate or vehicle were injected intraperitoneally daily from 1 day before the operation. Three days after the surgery, the effect of imatinib was assessed by physiological, morphological and molecular methods. The inhibition of PDGFRs against transforming growth factor-β1 (TGFB1)-induced fibrosis was also tested in human pericyte cell culture.Increased kidney weight and renal fibrosis were observed in the congested kidneys. Upstream inferior vena cava (IVC) pressure immediately increased to around 20 mmHg after IVC ligation in both the imatinib and saline groups. Although vasa recta dilatation and pericyte detachment under renal congestion were maintained, imatinib ameliorated the increased kidney weight and suppressed renal fibrosis around the vasa recta. TGFB1-induced elevation of fibrosis markers in human pericytes was suppressed by PDGFR inhibitors at the transcriptional level.The activation of the PDGFR pathway after renal congestion was responsible for renal congestion-induced fibrosis. This mechanism could be a candidate therapeutic target for renoprotection against renal congestion-induced tubulointerstitial injury.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic autoimmune disease characterized by necrotizing inflammation of the small blood vessels. ANCA-associated vasculitis is subclassified into three variants: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis (MPA). Myeloperoxidase (MPO) ANCA is a marker antibody for MPA. Interstitial pneumonia (IP) is occasionally complicated with MPA. However, only a few cases of idiopathic IP develop MPO-ANCA-positive conversion and MPA. Therefore, we present a case of a 70-year-old Japanese man with idiopathic IP who developed MPO-ANCA-positive conversion and MPA. We performed renal biopsy, which revealed pauci-immune crescentic glomerulonephritis. The patient was treated with intravenous methylprednisolone pulse therapy and oral prednisone, and the patient's laboratory data gradually improved with steroid therapy. The association between the production of MPO-ANCA and IP remains unclear, and the present case suggests that IP plays a role in inducing MPO-ANCA production. Patients with idiopathic IP should be followed-up carefully for an examination of increased MPO-ANCA levels and MPA development. In addition, early gastric cancer was detected during upper gastrointestinal endoscopy in our case, and it could also be important not to miss malignancy in patients with ANCA-associated vasculitis.

Fabry disease (FD) is an X-linked disorder of the sphingolipid metabolism, caused by deficiency or decreased activity of α-galactosidase A. We report a rare case of Fabry nephropathy (FN) in a 21-year-old Japanese female patient presenting with only urinary mulberry bodies; she was treated with pharmacological chaperone therapy (PCT) after renal biopsy. The patient underwent a detailed examination because her mother was diagnosed with FD in the Division of Community Medicine of our hospital. She did not have renal dysfunction or proteinuria, and only mulberry bodies were detected in the urine. The activity of α-galactosidase A was low, and genetic analysis revealed the R301Q mutation. A percutaneous renal biopsy was performed, and the findings revealed enlargement and vacuolation of glomerular podocytes by light microscopy, and myelin and zebra bodies were detected in podocytes by electron microscopy. She was diagnosed with FN by renal biopsy and gene analysis. PCT was selected as the treatment to prevent cardiac events and renal dysfunction. The present case suggests that renal biopsy may be necessary even for young women with only mulberry bodies for the diagnosis of FN. It could be useful to evaluate the effect of treatment using the counts of mulberry bodies in the urine. In addition, due to its oral administration, PCT may be suitable for patients who are unable to visit the hospital frequently.

This observational retrospective cohort study investigates the effect of antihypertensive therapy with angiotensin II receptor blockers (ARBs) or dihydropyridine calcium channel blockers (dCCBs) monotherapy on renal function using longitudinal real-world health data of a drug-naive, hypertensive population without kidney disease.Using propensity score matching, we selected untreated hypertensive participants ( n = 10 151) and dCCB ( n = 5078) or ARB ( n = 5073) new-users based on annual health check-ups and claims between 2008 and 2020. Participants were divided by the first prescribed drug.The mean age was 51 years, 79% were men and the mean estimated glomerular filtration rate (eGFR) was 78 ml/min per 1.73 m 2 . Blood pressure rapidly decreased by approximately 10% in both treatment groups. At the 1-year visit, eGFR levels decreased in the ARB group by nearly 2% but increased in the dCCB group by less than 1%. However, no significant difference was apparent in the annual eGFR change after the 1-year visit. The risk for composite kidney outcome (new-onset proteinuria or eGFR decline ≥30%) was lowest in the ARB group owing to their robust effect on preventing proteinuria: hazard ratio (95% confidence interval) for proteinuria was 0.91 (0.78-1.05) for the dCCB group and 0.54 (0.44-0.65) for the ARB group, compared with that for the untreated group after ending follow-up at the last visit before changing antihypertensive treatment.From the present findings based on the real-world data, ARBs can be recommended for kidney protection even in a primary care setting. Meanwhile, dCCB treatment initially increases eGFR with no adverse effects on proteinuria.

This study was performed to investigate the association of hypertension subtypes with glucose metabolism among the Japanese general population.The study involved 646 residents (mean age: 62.4 years) without treatment for hypertension or a history of diabetes from Ohasama, a rural Japanese community, who underwent an oral glucose tolerance test. Hypertension subtypes [normotension, isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic and diastolic hypertension (SDH)] were defined on the basis of home and office SBP and DBP (HBP and OBP, respectively). The estimated means of blood glucose related indices among the groups were compared by analysis of covariance adjusted for possible confounding factors.Blood glucose related indices were not different among the morning HBP-defined hypertension subtypes. Participants with evening HBP-defined ISH had a significantly higher estimated mean BG at 120 min, higher homeostasis model assessment-insulin resistance (HOMA-IR) and lower Matsuda-DeFronzo index than participants with NT (all P 0.021). Participants with OBP-defined SDH had a significantly higher estimated mean fasting blood glucose; blood glucose at 30, 60 and 120 min; and HOMA-IR and a lower Matsuda-DeFronzo index than participants with NT (all P 0.0025).The blood glucose related indices were different among hypertension subtypes. Participants with evening HBP-defined ISH and OBP-defined SDH had higher blood glucose levels and insulin resistance than participants with correspondingly defined normotension, while those with morning HBP did not. These findings suggest the importance of measuring evening HBP and office blood pressure for early detection of coexisting hypertension and diabetes.

Polycystic liver disease (PLD) is a hereditary liver disease in which the number of cysts increases over time, causing various abdominal symptoms and poor quality of life. Although effective treatment for PLD has not been established, we recently reported that long-term exercise ameliorated liver cyst formation and fibrosis with the activation of AMP-activated protein kinase (AMPK) in polycystic kidney (PCK) rats, a PLD model. Therefore, the aim of this study was to investigate whether metformin, an indirect AMPK activator, was effective in PCK rats. PCK rats were randomly divided into a control (Con) group and a metformin-treated (Met) group. The Met group was treated orally with metformin in drinking water. After 12 wk, liver function, histology, and signaling cascades of PLD were examined in the groups. Metformin did not affect the body weight or liver weight, but it reduced liver cyst formation, cholangiocyte proliferation, and fibrosis around the cyst. Metformin increased the phosphorylation of AMPK and tuberous sclerosis complex 2 and decreased the phosphorylation of mammalian target of rapamycin, S6, and extracellular signal-regulated kinase and the expression of cystic fibrosis transmembrane conductance regulator, aquaporin I, transforming growth factor-β, and type 1 collagen without changes in apoptosis or collagen degradation factors in the liver. Metformin slows the development of cyst formation and fibrosis with the activation of AMPK and inhibition of signaling cascades responsible for cellular proliferation and fibrosis in the liver of PCK rats.

Lifetime risk (LTR) evaluates the absolute risk of developing a disease during the remainder of one’s life. It can be a useful tool, enabling the general public to easily understand their risk of stroke. No study has been performed to determine the LTR of cardiovascular disease in patients with chronic kidney disease (CKD) with or without hypertension; therefore, we performed this study in an Asian population. We followed 1525 participants (66.0% women; age 63.1 years) in the general population of Ohasama, Japan. We defined CKD as an estimated glomerular filtration rate (eGFR)

A patient with polycystic kidney disease had flank and back pain lasting for a month. We considered that her cysts led to the pain, which is a common symptom of polycystic kidney disease. However, a cancer hidden in large and multiple cysts caused the pain.

A 65-year-old woman was hospitalized for heart failure and pneumonia in a nearby hospital. She had been previously diagnosed as light chain (AL) amyloidosis and treated with melphalan plus dexamethasone (Mel-Dex), and lenalidomide plus dexamethasone (Len-Dex). She started treatment including antimicrobials and diuretics, but her renal function worsened progressively, and she was transferred to our hospital for nephrological care. She was treated with antimicrobials, noradrenaline, dobutamine, and continuous hemodiafiltration. Her general condition gradually stabilized, and she was switched to intermittent hemodialysis (HD). However, HD was discontinued due to intradialytic hypotension and the development of heparin-induced thrombocytopenia. Her renal replacement therapy was switched to peritoneal dialysis (PD), which enabled good volume control and stable cardiac function. She was discharged and is still in good condition, without serious complications and achieving a considerably better prognosis than was predicted. Our case suggests that PD is an effective modality for patients with AL amyloidosis with heart failure and renal dysfunction.

No studies have demonstrated the association between urinary sodium-to-potassium (Na/K) ratio and all out-of-office blood pressure (BP) [home morning and evening BP (self-measured at home), and 24-h, daytime, and night-time ambulatory BP] in the same cohort. We aimed to assess, which type of out-of-office BP is more strongly associated with urinary Na/K ratio in the general population.This cross-sectional study was conducted in the general population of Ohasama, Japan. Home and ambulatory BP levels were measured, and 24-h urine samples were obtained from 875 participants (men, 25.5%; mean age, 60.1 years). The urinary Na/K ratio in the 24-h urine samples was calculated.The median (interquartile range) urinary Na/K ratio was 4.19 (3.36-5.26). Significant positive trends of home morning, home evening, 24-h, and daytime SBP were observed across quartiles of urinary Na/K ratio (trend P 0.041; adjusted mean values between Q1 and Q4 of urinary Na/K ratio: 121.0-125.5 mmHg for home morning, 120.1-123.8mmhg for home evening, 121.6-123.4mmHg for 24-h, 127.5-129.5 mmHg for daytime). Urinary Na/K ratio was not significantly associated with office or night-time SBP and nocturnal BP fall (trend P 0.13). In the model with both home morning or evening SBP and daytime SBP, only home SBP was significantly associated with urinary Na/K ratio (P 0.048 for home SBP).These findings suggest that urinary Na/K ratio might be more strongly associated with home BP than with 24-h and daytime BP but was not associated with night-time BP.

Nephrolithiasis is a common renal disease with no effective medication. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, an anti-diabetic agent, have diuretic and anti-inflammatory properties and could prevent nephrolithiasis. Here, we investigated the potential of SGLT2 inhibition against nephrolithiasis using large-scale epidemiological data, animal models, and cell culture experiments.This study included the data of diabetic patients (n = 1,538,198) available in the Japanese administrative database and divided them according to SGLT2 inhibitor prescription status. For animal experiments, renal calcium oxalate stones were induced by ethylene glycol in Sprague-Dawley rats, and phlorizin, an SGLT1/2 inhibitor, was used for the treatment. The effects of SGLT2-specific inhibition for renal stone formation were assessed in SGLT2-deficient mice and a human proximal tubular cell line, HK-2.Nephrolithiasis prevalence in diabetic men was significantly lower in the SGLT2 inhibitor prescription group than in the non-SGLT2 inhibitor prescription group. Phlorizin attenuated renal stone formation and downregulated the kidney injury molecule 1 (Kim1) and osteopontin (Opn) expression in rats, with unchanged water intake and urine volume. It suppressed inflammation and macrophage marker expression, suggesting the role of the SGLT2 inhibitor in reducing inflammation. SGLT2-deficient mice were resistant to glyoxylic acid-induced calcium oxalate stone formation with reduced Opn expression and renal damages. High glucose-induced upregulation of OPN and CD44 and cell surface adhesion of calcium oxalate reduced upon SGLT2-silencing in HK-2 cells.Overall, our findings identified that SGLT2 inhibition prevents renal stone formation and may be a promising therapeutic approach against nephrolithiasis.

Alport syndrome is an inherited chronic human kidney disease, characterized by glomerular basement membrane abnormalities. This disease is caused by mutations in COL4A3, COL4A4, or COL4A5 gene. The knockout mice for Col4α3, Col4α4, and Col4α5 are developed and well characterized for the study of Alport syndrome. However, disease progression and effects of pharmacological therapy depend on the genetic variability. This model was reliable only to mouse. In this study, we created a novel Alport syndrome rat model utilizing the rGONAD technology, which generated rat with a deletion of the Col4α5 gene. Col4α5 deficient rats showed hematuria, proteinuria, high levels of BUN, Cre, and then died at 18 to 28 weeks of age (Hemizygous mutant males). Histological and ultrastructural analyses displayed the abnormalities including parietal cell hyperplasia, mesangial sclerosis, and interstitial fibrosis. Then, we demonstrated that α3/α4/α5 (IV) and α5/α5/α6 (IV) chains of type IV collagen disrupted in Col4α5 deficient rats. Thus, Col4α5 mutant rat is a reliable candidate for the Alport syndrome model for underlying the mechanism of kidney diseases and further identifying potential therapeutic targets for human renal diseases.

Alport syndrome is an inherited chronic human kidney disease, characterized by glomerular basement membrane abnormalities. This disease is caused by mutations in COL4A3, COL4A4, or COL4A5 gene. The knockout mice for Col4α3, Col4α4, and Col4α5 are developed and well characterized for the study of Alport syndrome. However, disease progression and effects of pharmacological therapy depend on the genetic variability. This model was reliable only to mouse. In this study, we created a novel Alport syndrome rat model utilizing the rGONAD technology, which generated rat with a deletion of the Col4α5 gene. Col4α5 deficient rats showed hematuria, proteinuria, high levels of BUN, Cre, and then died at 18 to 28 weeks of age (Hemizygous mutant males). Histological and ultrastructural analyses displayed the abnormalities including parietal cell hyperplasia, mesangial sclerosis, and interstitial fibrosis. Then, we demonstrated that α3/α4/α5 (IV) and α5/α5/α6 (IV) chains of type IV collagen disrupted in Col4α5 deficient rats. Thus, Col4α5 mutant rat is a reliable candidate for the Alport syndrome model for underlying the mechanism of kidney diseases and further identifying potential therapeutic targets for human renal diseases.

(Pro)renin receptor [(P)RR] is a component of the renin-angiotensin system and plays an essential role in the activity of vacuolar H+-ATPase and autophagy. (P)RR is expressed in cancer cells. However, the relationship among (P)RR, apoptosis and autophagy in the treatment of anti-cancer drugs has not been clarified. The aim of this study was to clarify the effects of anti-cancer drugs with autophagy-promoting activity on (P)RR expression in cancer cells. MCF-7 breast cancer cells and A549 lung cancer cells were treated with carboplatin or paclitaxel, and the expression of (P)RR, apoptosis markers and autophagy markers were assessed by RT-qPCR, western blot analysis and immunocytochemistry. Expression levels of (P)RR mRNA and soluble (P)RR protein were increased by carboplatin or paclitaxel in a dose-dependent manner. Immunofluorescence staining of (P)RR was increased in both MCF-7 and A549 cells treated by carboplatin or paclitaxel. Apoptosis induction was shown by elevated BAX/BCL2 mRNA levels and increased active caspase3-positive cells. Moreover, autophagy induction was confirmed by increased levels of autophagy-associated mRNAs and LC3B-II proteins. (P)RR knockdown by (P)RR-specific siRNA suppressed the cell viability in MCF-7 cells and A549 cells under the treatment of carboplatin or paclitaxel, suggesting that (P)RR deficiency inhibits the proliferation of cancer cells in a pathway different from carboplatin or paclitaxel. The present study showed that the expression of (P)RR mRNA and soluble (P)RR was increased by anti-cancer drugs with autophagy-promoting activity. Upregulated (P)RR and autophagy may constitute a stress adaptation that protects cancer cells from apoptosis.

The number of patients aged ≥ 75 years and who need renal replacement therapy is steadily increasing. The study aimed to determine the safety of open surgery for peritoneal dialysis (PD) catheter placement in such patients.This prospective cohort study included patients who underwent PD catheter placement by open surgery under dexmedetomidine (DEX) and local anesthesia at our institution from January 2015 to February 2021. Patients were divided into the following two groups according to age at the time of surgery: ≥ 75 years (group A) and 75 years (group B). We compared the perioperative and postoperative complications (i.e., time to the first PD-related peritonitis and catheter obstruction requiring surgical intervention within 1 year) between the groups.A total of 118 patients were categorized into groups A (n = 65) and B (n = 53). No significant intergroup differences were observed in the postoperative fever, total duration of surgery, perioperative hemoglobin decrease, changes in the white blood cell count and C-reactive protein, postoperative catheter leakage, postoperative hospital stay, time to the first PD-related peritonitis, and catheter obstruction requiring surgical intervention within 1 year.The surgery for PD catheter placement by open surgery under DEX and local anesthesia in elderly patients is safe and effective.

Peritoneal dialysis (PD) catheter malposition is one of the complications of renal replacement therapy. This study aimed to determine the preoperative factors that cause PD catheter malposition.The prospective cohort study included patients who underwent PD catheter insertion surgery and had preoperative and postoperative computed tomography scans. We compared preoperative and intraoperative factors between the lower depth catheter group (group L) and upper depth catheter group (group U), and preoperative and intraoperative factors between the posterior catheter group (group P) and anterior catheter group (group A). In addition, PD catheter obstruction requiring surgical intervention in each group was followed up for 1 year.A total of 150 patients were categorized into groups L (n = 77) and U (n = 73), or groups P (n = 107) and A (n = 43). Body mass index (BMI; P = 0.02), subcutaneous fat area (P = 0.02), and rate of previous abdominal surgery (P = 0.01) were significantly lower in group L than in group U. In terms of anterior catheter position, females had more-anterior catheter positions. The time to PD catheter obstruction requiring surgical intervention (P = 0.03) was significantly lower in group U than in group L.High BMI, high subcutaneous fat area, high subcutaneous fat thickness, and previous abdominal surgery were identified as preoperative factors that cause the PD catheter to have an upper depth. Female sex was a preoperative influencing factor for the anterior PD catheter position.

Background We aimed to develop risk prediction models for new-onset home morning hypertension. Methods We followed up 978 participants without home hypertension in the general population of Ohasama, Japan (men: 30.1%, age: 53.3 years). The participants were divided into derivation (n = 489) and validation (n = 489) cohorts by their residential area. The C-statistics and calibration plots were assessed after the 5- or 10-year follow-up. Results In the derivation cohort, sex, age, body mass index, smoking, office systolic blood pressure (SBP), and home SBP at baseline were selected as significant risk factors for new-onset home hypertension (≥135/85 mm Hg or the initiation of antihypertensive treatment) using the Cox model. In the validation cohort, Harrell’s C-statistic for the 5-/10-year home hypertension was 0.7637 (0.7195–0.8100)/0.7308 (0.6932–0.7677), when we used the full model, which included the significant risk factors in the derivation cohort. The calibration test revealed good concordance between the observed and predicted 5-/10-year home hypertension probabilities (P ≥ 0.19); the regression slope of the observed probability on the predicted probability was 1.10/1.02, and the intercept was −0.04/0.06, respectively. A model without home SBP was also developed; for the 10-year home hypertension risk, the calibration test revealed a good concordance (P = 0.19) but Harrell’s C-statistic was 0.6689 (0.6266–0.7067). Conclusions The full model revealed good ability to predict the 5- and 10-year home morning hypertension risk. Although the model without home SBP is acceptable, the low C-statistic implies that home BP should be measured to predict home morning hypertension precisely.

Vacuolar H(+)-ATPase–dependent (V-ATPase–dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell–derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase–dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase–dependent signaling and protein degradation in the developing human central nervous system.

Background and Aims While previous studies have reported the association between serum uric acid (SUA) and chronic kidney disease (CKD) incidence, the sex differences in this association remain controversial. Therefore, we examined the association between SUA levels and CKD incidence in middle-aged adults stratified by sex using data from a large-scale health check-up. Method We analyzed information from the JMDC database, which included the annual health check-up data of Japanese employees and their dependents aged Results The mean participant age was 44.1 years, and 29.6% were women. The mean SUA levels were 5.9 mg/dL and 4.1 mg/dL in men and women, respectively. During the mean follow-up period of 4.68 years, 12,589 participants developed CKD. The age-standardized incidence rates for CKD were 17.88/17.80 per 1000 person-years in men/women with SUA concentrations of 4.0–4.9 mg/dL, 209.76 per 1000 person-years in men with SUA ≥11.0 mg/dL, and 73.38 per 1000 person-years in women with SUA ≥ 9.0 mg/dL. The fully adjusted HRs (95% confidence interval [CI], P value) for CKD incidence in the groups with SUA concentrations of Conclusion The results of the present study demonstrated an increased risk of CKD in men with SUA concentrations of

SummaryAlport syndrome is an inherited chronic human kidney disease, characterized by glomerular basement membrane abnormalities. This disease is caused by mutations in COL4A3, COL4A4, or COL4A5 gene. The knockout mice for Col4α3, Col4α4, and Col4α5 are developed and well characterized for the study of Alport syndrome. However, disease progression and effects of pharmacological therapy depend on the genetic variability. This model is reliable only to mice. Therefore in this study, we created a novel Alport syndrome rat model utilizing rGONAD technology. Col4α5 deficient rats showed hematuria, proteinuria, high levels of BUN, Cre, and then died at 18 to 28 weeks of age (Hemizygous mutant males). Histological and ultrastructural analyses displayed the abnormalities including parietal cell hyperplasia, mesangial sclerosis, and interstitial fibrosis. Then, we demonstrated that α3/α4/α5 (IV) and α5/α5/α6 (IV) chains of type IV collagen disrupted in the Col4α5 deficient rats. Moreover, immunofluorescence analyses revealed that some glomeruli of Col4α5 mutant rats were found to be disrupted from postnatal day 0. Thus, Col4α5 mutant rat is a reliable candidate for Alport syndrome model for underlying the mechanism of renal diseases and further identifying potential therapeutic targets for human renal diseases.

Chronic kidney disease (CKD) is a global health burden. Previous studies have shown a J- or U-shaped association between serum uric acid (SUA) and cardiovascular mortality. We assessed the risk of CKD incidence in a refined SUA category in middle-aged adults stratified by sex.We analyzed data from 138,511 participants65 years old (29.6% women; mean age 44.1 years) without CKD at baseline acquired from the JMDC database. The Cox model was used to assess the adjusted hazard ratio (HR).During the mean follow-up period of 4.68 years, 12,589 participants developed CKD. The fully adjusted HRs (95% confidence interval [CI], p-value) for CKD incidence in men with SUA4.0, 10.0-10.9 and ≥ 11.0 mg/dL compared to men with SUA 4.0-4.9 mg/dL were 1.13 (1.01-1.26, p = 0.030), 1.98 (1.32-2.97, p = 0.0010), and 3.74 (1.68-8.35, p = 0.0013), respectively. The fully adjusted HRs for CKD incidence in women with SUA4.0, 8.0-8.9, and ≥9.0 mg/dL compared to women with SUA 4.0-4.9 mg/dL were 1.08 (1.01-1.16, p = 0.032), 2.39 (1.07-5.35, p = 0.034), and 3.20 (0.80-12.8, p = 0.10), respectively.Both high and low SUA levels were identified as risk factors for CKD incidence in middle-aged men and women. The association of SUA levels with the increase in the risk of CKD incidence differed by sex, and the range of SUA levels associated with an increase in the risk of CKD incidence varied by sex.

White coat hypertension is defined as elevated blood pressure in the office, but a normal blood pressure out-of-office, whereas masked hypertension is defined as elevated blood pressure in the office, but normal out-of-office blood pressure. The objective was to investigate the associations between these blood pressure phenotypes and carotid artery changes. Conventional blood pressure, ambulatory blood pressure, and carotid ultrasonography were evaluated in 851 Ohasama residents (31.8% men; mean age 66.3 years). The blood pressure phenotypes were defined by the ordinary thresholds (140/90 mmHg for conventional blood pressure, 135/85 mmHg for daytime blood pressure) and then by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) thresholds for hypertension (130/80 mmHg for both conventional and daytime blood pressure), irrespective of antihypertensive medication treatment status. Blood pressure phenotypes were linearly associated with the mean intima-media thickness of the carotid artery in ascending order for sustained normal blood pressure, white coat hypertension, masked hypertension, and sustained hypertension according to the ordinary thresholds and the 2017 ACC/AHA thresholds (both linear trends P < 0.0001) after adjustments for possible confounding factors. The odds ratios for the presence of carotid plaques showed similar linear trends with the blood pressure phenotypes according to the 2017 ACC/AHA thresholds (linear trend P < 0.0191). In conclusion, there was a close relationship between blood pressure phenotypes and carotid artery changes, suggesting that blood pressure phenotypes as defined by ambulatory blood pressure are potentially useful for risk stratification of carotid artery changes in the Japanese general population. ispartof: TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE vol:252 issue:3 pages:269-279 ispartof: location:Japan status: published

Renal venous congestion by increased central venous pressure in congestive heart failure is responsible for renal dysfunction. We have created a novel rat renal congestion model presenting increased renal interstitial hydrostatic pressure and vasa recta expansion, which leads to renal congestion-mediated fibrosis. Current clinical trials suggest the renoprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in heart failure patients; however, the underlying mechanisms are still discussing. Thus, we investigated the effect of phlorizin, a commercially available SGLT1/2 inhibitor, in our renal congestion model. All animal procedures were performed in accordance with the policies and guidelines of the “Position of the American Heart Association on Research Animal Use” and were approved by the Tohoku Medical and Pharmaceutical University Animal Experiment Committee (registration number: A18019-a, A19039-cn and A20005-cn). The inferior vena cava between the renal veins was ligated, which induced congestion only in the left kidney. Phlorizin (400 mg/kg body weight) or saline were injected subcutaneously daily from 1 day before the operation. Both the right control kidney and left congested kidney were collected 3 days after the surgery. Increased kidney weight and renal fibrosis were observed in the congested kidneys. Phlorizin attenuated the increased kidney weight and suppressed renal fibrosis staining. Molecules related to kidney injury (Kim1) and fibrosis (Fn1 and αSma) were also suppressed by Phlorizin in the congested kidney. Low-vacuum electron microscopy revealed the vasa recta dilatation in the congested kidney. This morphological change was alleviated by Phlorizin. These results suggest that SGLT1/2 inhibitor could suppress renal congestion-mediated fibrosis. This mechanism could be a potential therapeutic target for renoprotection against heart failure.

Lifetime risk (LTR) evaluates the absolute risk of developing a disease during the remainder of one's life. It can be a useful tool, enabling the general public to easily understand their risk of stroke. No study has been performed to determine the LTR of cardiovascular disease in patients with chronic kidney disease (CKD) with or without hypertension; therefore, we performed this study in an Asian population. We followed 1525 participants (66.0% women; age 63.1 years) in the general population of Ohasama, Japan. We defined CKD as an estimated glomerular filtration rate (eGFR)60 mL/min/1.73 m

(Pro)renin receptor ((P)RR)/ ATP6AP2 (ATPase, H+ transporting, lysosomal accessory protein 2) functions as an essential accessory subunit of vacuolar H+ -ATPase (V-ATPase). V-ATPase is necessary for lysosome function and autophagy. Autophagy is related to cell proliferation, migration and invasion of various cancer cells. In this study, we aim to clarify the relationship between (P)RR and autophagy in lung adenocarcinoma. Expression of (P)RR and Ki-67 (a proliferation marker) was studied in sixty-four adenocarcinoma cases by immunohistochemistry. Lung adenocarcinoma cell line, A549, was transfected with (P)RR-specific siRNA. Autophagy inhibitors, bafilomycin A1 and chloroquine, were used as positive controls. Cell proliferation and migration were measured by WST-8 assay and wound healing assay. Autophagosome markers, p62 and LC3, were analyzed by RT-qPCR, Western blot and immunocytochemistry. Immunohistochemistry showed that (P)RR was expressed in all adenocarcinoma tissues. The intensity of (P)RR immunoreactivity was significantly associated with Ki-67. Treatment of (P)RR-specific siRNA suppressed (P)RR expression and significantly reduced cell proliferation and migration as did the autophagy inhibitors. Western blot and immunocytochemistry showed that (P)RR-specific siRNA, as well as the autophagy inhibitors, induced p62 and LC3 accumulation in cytoplasmic granules. These results suggest that (P)RR is involved in cell proliferation and progression of lung adenocarcinoma via regulating autophagy.

The (P)RR ([pro]renin receptor) was identified as a new component of the renin-angiotensin system. We previously reported that high salt (HS) intake increased the (P)RR expression in several nephron segments of Sprague-Dawley rats. Other studies reported HS intake increased the XO (xanthine oxidase) activity and an MR (mineralocorticoid receptor) antagonist inhibited HS intake–increased (P)RR expression in the kidneys of Dahl salt-sensitive (DS) rats. The present study examined the effects of HS intake on (P)RR expression in the kidney of DS rats. Male DS rats were fed a normal salt diet or an HS diet for 4 weeks. Some of the rats fed on the HS diet were treated with the XO inhibitor, febuxostat, and the MR antagonist, spironolactone. Immunoblot and immunohistochemical analyses showed that HS intake increased (P)RR expression in the renal cortex by 22.6-fold, the proximal tubules by 4.9-fold and the distal tubules, respectively. Both febuxostat and spironolactone inhibited HS intake–increased (P)RR expression in the renal cortex. Febuxostat inhibited HS intake–increased (P)RR expression in the proximal tubules, whereas spironolactone inhibited HS intake–increased (P)RR expression in the distal tubules. Additionally, deoxycorticosterone acetate increased (P)RR expression in the renal cortex and distal tubules but not in the proximal tubules of DS rats fed the normal salt diet. These results indicate that HS intake greatly increases (P)RR expression in the renal cortex of DS rats. The mechanisms of HS intake–increased (P)RR expression may work in an XO-dependent manner in the proximal tubules and an MR-dependent manner in the distal tubules.