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2. Cover Image

Author

Su, Xiao-Tong, Reyes, Jeremiah V., Lackey, Anne E., Demirci, Hasan, Bachmann, Sebastian, Maeoka, Yujiro, Cornelius, Ryan J., McCormick, James A., Yang, Chao-Ling, Jung, Hyun Jun, Welling, Paul A., Nelson, Jonathan W., and Ellison, David H.

Published
2024
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6. Distal convoluted tubule-specific disruption of the COP9 signalosome but not its regulatory target cullin 3 causes tubular injury.

Author

Maeoka, Yujiro, Bradford, Tanner, Su, Xiao-Tong, Sharma, Avika, Yang, Chao-Ling, Ellison, David H., McCormick, James A., and Cornelius, Ryan J.

Subjects
GENETIC disorders, KIDNEY injuries, ACIDOSIS, PREVENTION of injury, KIDNEY tubules
Abstract

The disease familial hyperkalemic hypertension (FHHt; also known as Gordon syndrome) is caused by aberrant accumulation of with-no-lysine kinase (WNK4) activating the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) of the kidney. Mutations in cullin 3 (CUL3) cause FHHt by disrupting interaction with the deneddylase COP9 signalosome (CSN). Deletion of Cul3 or Jab1 (the catalytically active CSN subunit) along the entire nephron causes a partial FHHt phenotype with activation of the WNK4-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NCC pathway. However, progressive kidney injury likely prevents hypertension, hyperkalemia, and hyperchloremic metabolic acidosis associated with FHHt. We hypothesized that DCT-specific deletion would more closely model the disease. We used Slc12a3-Cre-ERT2 mice to delete Cul3 (DCT-Cul3−/−) or Jab1 (DCT-Jab1−/−) only in the DCT and examined the mice after short- and long-term deletion. Short-term DCT-specific knockout of both Cul3 and Jab1 mice caused elevated WNK4, pSPAKS373, and pNCCT53 abundance. However, neither model demonstrated changes in plasma K+, Cl−, or total CO2, even though no injury was present. Long-term DCT-Jab1−/− mice showed significantly lower NCC and parvalbumin abundance and a higher abundance of kidney injury molecule-1, a marker of proximal tubule injury. No injury or reduction in NCC or parvalbumin was observed in long-term DCT-Cul3−/− mice. In summary, the prevention of injury outside the DCT did not lead to a complete FHHt phenotype despite activation of the WNK4-SPAK-NCC pathway, possibly due to insufficient NCC activation. Chronically, only DCT-Jab1−/− mice developed tubule injury and atrophy of the DCT, suggesting a direct JAB1 effect or dysregulation of other cullins as mechanisms for injury. NEW & NOTEWORTHY: CUL3 degrades WNK4, which prevents activation of NCC in the DCT. CSN regulation of CUL3 is impaired in the disease FHHt, causing accumulation of WNK4. Short-term DCT-specific disruption of CUL3 or the CSN in mice resulted in activation of the WNK4-SPAK-NCC pathway but not hyperkalemic metabolic acidosis found in FHHt. Tubule injury was observed only after long-term CSN disruption. The data suggest that disruption of other cullins may be the cause for the injury. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Role of Angiotensin II Type 1a Receptor (AT1aR) of Renal Tubules in Regulating Inwardly Rectifying Potassium Channels 4.2 (Kir4.2), Kir4.1, and Epithelial Na + Channel (ENaC)

Author

Duan, Xin-Peng, primary, Xiao, Yu, additional, Su, Xiao-Tong, additional, Zheng, Jun-Ya, additional, Gurley, Susan, additional, Emathinger, Jacqueline, additional, Yang, Chao-Ling, additional, McCormick, James, additional, Ellison, David H., additional, Lin, Dao-Hong, additional, and Wang, Wen-Hui, additional

Published
2024
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18. Effects of methoxy polyethylene glycol‐polycaprolactone block copolymers and silica nanoparticles on the mechanical, tissue affinity and antibacterial properties of n‐butyl cyanoacrylate adhesive.

Author

Su, Xiao‐Tong, Jin, Guo‐Cheng, and Xu, Shi‐Ai

Subjects
BLOCK copolymers, SILICA nanoparticles, POLYCAPROLACTONE, ESCHERICHIA coli, ADHESIVES, POLYETHYLENE
Abstract

Cyanoacrylates are widely used as surgical tissue adhesives because of their high biodegradability, but they are brittle and have poor tissue affinity. In this study, methoxy polyethylene glycol‐polycaprolactone block copolymers (MPEG‐co‐PCLs) with different PCL chain lengths were synthesized by ring‐opening polymerization. Then, a new tissue adhesive with excellent mechanical properties, tissue affinity, antibacterial properties, and coagulation performances was prepared by incorporating MPEG‐co‐PCL and silica nanoparticles (SNPs) into n‐butyl cyanoacrylate (BCA). The optimal MPEG: PCL ratio is 1:4 (MP‐3), and the optimal mass ratio of MPEG‐co‐PCL and SNPs (0.5SNPs/0.5MP‐3) is 0.5 wt.%. Compared to BCA, the adhesion strength and flexibility of 0.5SNPs/0.5MP‐3 are dramatically improved by 110% and 244%, respectively. MPEG‐co‐PCL can fully exploit the advantages of homopolymers, and therefore, improve the tissue affinity and adhesion strength of the adhesive and avoid BCA polymerization initiated by MPEG and poor compatibility of PCL with BCA. SNPs can also compensate for the lack of antibacterial properties of BCA against Gram‐negative bacteria. The E. coli inhibition circle of 0.5SNPs/0.5MP‐3 is twice as large as BCA. SNPs can also improve coagulation by promoting platelet aggregation. This work provides an effective strategy for developing adhesives with potential clinical applications. [ABSTRACT FROM AUTHOR]

Published
2023
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26. Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

Author

Maeoka, Yujiro, primary, Ferdaus, Mohammed Z., additional, Cornelius, Ryan J., additional, Sharma, Avika, additional, Su, Xiao-Tong, additional, Miller, Lauren N., additional, Robertson, Joshua A., additional, Gurley, Susan B., additional, Yang, Chao-Ling, additional, Ellison, David H., additional, and McCormick, James A., additional

Published
2022
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28. MO442ACUTE ADVERSE EFFECTS OF LOW POTASSIUM ON HEART AND KIDNEY*

Author

Saritas, Turgay, primary, Chen, Lu, additional, Babler, Anne, additional, Rix, Anne, additional, Reimer, Katharina C, additional, Jansen, Jitske, additional, Su, Xiao-Tong, additional, Kerker, Andrew S, additional, Cuevas, Catherina A, additional, Menzel, Sylvie, additional, Kuppe, Christoph, additional, Boor, Peter, additional, Falke, Lucas, additional, Bleilevens, Christian, additional, McCormick, James, additional, Floege, Jürgen, additional, Ellison, David H, additional, and Kramann, Rafael, additional

Published
2021
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35. Long-term disruption of the COP9 Signalosome decreases NCC abundance due to remodeling of the distal nephron

Author

Cornelius, Ryan J., Nelson, Jonathan W., Su, Xiao-Tong, Chao-Ling Yang, and Ellison, David H.

Subjects
Pseudohypoaldosteronism Type II, urogenital system, Nephrology, Cullin 3, FHHt, Hypertension, Familial Hyperkalemic Hypertension, PHAII, Blood Pressure, Cullin-RING Ubiquitin Ligase
Abstract

The cullin 3 mutant that causes human familial hyperkalemic hypertension increases WNK abundance, activating the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). Previous work determined that the mutation impairs binding to the deneddylase COP9 signalosome (CSN), which might contribute to the disease pathogenesis. In vivo disruption of the CSN using a nephron-specific, inducible mouse model in which the catalytic subunit, JAB1, is deleted (KS-Jab1-/- mice), resulted, however, in a mixed phenotype with WNK activation, but decreased NCC abundance. To test the hypothesis that the effects on NCC are secondary to tubule damage or remodeling, mice were given doxycycline in their drinking water for 3 weeks (w), to induce genetic deletion of Jab1, and were analyzed at 0 w, 1 w, 2 w and 3 w post treatment (PT). Western blotting for WNK4 showed an increase in protein abundance at 0 w PT compared to control, and a significantly higher abundance at each subsequent time point. Consistent with WNK4 activation, the abundance of phosphorylated NCC (pNCC) was greater at 0 w, 1 w, 2 w PT. Total NCC abundance was unchanged at 0 w, 1 w, and 2 w PT, but was significantly lower at 3 w PT. To examine if the late effect on NCC results from DCT remodeling, we used kidney clearing (ethyl cinnamate) with confocal imaging, using antibodies against pNCC to capture three dimensional images of the DCT and measure tubule length. At 0 w PT, DCT length was unchanged compared to control (423.3 ± 25.64 vs. 406.5 ± 21.2 μm), but was significantly shorter in mice at 3 w PT (276.1 ± 18.1 μm, P < 0.01). Along with a shorter DCT length, the number of pNCC-positive tubules was substantially lower at 3 w PT compared to control, suggesting tubule dropout. Immunofluorescent staining for kidney injury molecule-1 (KIM-1) showed similar intensity in the cortex at 0 w and 3 w PT compared to control, indicating that the long-term effects of CSN disruption on the DCT is not caused by tubule damage. However, KIM-1 staining intensity was high in the outer medulla at 0 w and remained so at 3 w PT, suggesting tubule damage at this site. This may have contributed to increased urine output of KS-Jab1-/- mice (control: 5.28 ± 0.29 vs. 0 w: 9.16 ± 1.83 ml/d, P < 0.01) and mitigated the FHHt phenotype. Quantitative real-time PCR measurements demonstrated that mRNA expression for the DCT markers NCC and parvalbumin showed a linear decrease over time (NCC 18% of control at 3 w PT; parvalbumin 8% of control). Interestingly, mRNA expression for the proximal tubule marker, NHE3, and thick ascending limb marker, NKCC2, was not significantly different at 0 w and 1 w PT, however, at 2 w and 3 w PT mRNA levels were approximately 50% of control, suggesting that nephron remodeling/tubule dropout is not limited to the DCT. The results show that in vivo disruption of the CSN mimics many aspects of familial hyperkalemic hypertension, but also leads to tubule damage and nephron remodeling; the latter is likely absent in human disease, owing to its autosomal dominant pathogenesis., This poster was presented at the Experimental Biology (EB) Conference on April 6-9, 2019 by Ryan J. Cornelius.

Published
2019
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42. WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia

Author

Thomson, Martin N., primary, Cuevas, Catherina A., additional, Bewarder, Tim M., additional, Dittmayer, Carsten, additional, Miller, Lauren N., additional, Si, Jinge, additional, Cornelius, Ryan J., additional, Su, Xiao-Tong, additional, Yang, Chao-Ling, additional, McCormick, James A., additional, Hadchouel, Juliette, additional, Ellison, David H., additional, Bachmann, Sebastian, additional, and Mutig, Kerim, additional

Published
2020
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43. AT2R-mediated regulation of Na-Cl cotransporter (NCC) and renal K excretion depends on the K channel, Kir4.1

Author

Wu, Peng, Gao, Zhong-Xiuzi, Duan, Xin-Peng, Su, Xiao-Tong, Wang, Ming-Xiao, Lin, Dao-Hong, Gu, Ruimin, and Wang, Wen-Hui

Subjects
Sodium, Potassium, Solute Carrier Family 12, Member 3, Receptor, Angiotensin, Type 2, Article, Receptor, Angiotensin, Type 1
Abstract

Angiotensin II (AngII) type 2 receptor (AT2R) is expressed in the distal nephrons. The aim of the present study is to examine whether AT2R regulates Na-Cl cotransporter (NCC) and Kir4.1 of the distal convoluted tubule (DCT). AngII inhibited the basolateral 40 pS K channel (a Kir4.1/5.1 heterotetramer) in the DCT treated with losartan but not with PD123319. AT2R agonist also inhibits the K channel, indicating that AT2R was involved in tonic regulation of Kir4.1. The infusion of PD123319 stimulated the expression of total NCC (tNCC) and phosphorylated NCC (pNCC) (Thr(53)) by a time-dependent way with the peak at 4 days. PD123319 treatment (4 days) stimulated the basolateral 40 pS K channel activity, augmented the basolateral K conductance and increased the negativity of DCT membrane. The stimulation of Kir4.1 was essential for PD123319-induced increase in NCC since inhibiting AT2R increased the expression of tNCC and pNCC only in WT but not in the kidney-specific Kir4.1 knockout (KS-Kir4.1 KO) mice. Renal clearance study showed that thiazide-induced natriuretic effect was larger in PD123319 treated mice for 4 days than untreated mice. However, this effect was absent in KS-Kir4.1 KO mice which were also Na wasting under basal conditions. Finally, application of AT2R antagonist decreased the renal ability of K excretion and caused hyperkalemia in WT but not in KS-Kir4.1 KO mice. We conclude that AT2R dependent regulation of NCC requires Kir4.1 in the DCT and that AT2R plays a role in stimulating K excretion by inhibiting Kir4.1 and NCC.

Published
2018

48. Potassium (K+) intake modulates NCC activity via the K+ channel, Kir4.1

Author

Wang, Ming-Xiao, Gallardo, Catherina Cuevas, Su, Xiao-Tong, Wu, Peng, Gao, Zhong-Xiuzi, Lin, Dao-Hong, McCormick, James A., Yang, Chao-Ling, Wang, Wen-Hui, and Ellison, David H.

Subjects
Male, Mice, Knockout, Sodium Chloride Symporter Inhibitors, Sodium, Natriuresis, Potassium, Dietary, Alkalosis, Hypokalemia, Article, Membrane Potentials, Disease Models, Animal, Renal Elimination, Hydrochlorothiazide, Animals, Homeostasis, Female, Solute Carrier Family 12, Member 3, Potassium Channels, Inwardly Rectifying, Kidney Tubules, Distal
Abstract

Kir4.1 in the distal convoluted tubule plays a key role in sensing plasma potassium and in modulating the thiazide-sensitive sodium-chloride cotransporter (NCC). Here we tested whether dietary potassium intake modulates Kir4.1 and whether this is essential for mediating the effect of potassium diet on NCC. High potassium intake inhibited the basolateral 40 pS potassium channel (a Kir4.1/5.1 heterotetramer) in the distal convoluted tubule, decreased basolateral potassium conductance, and depolarized the distal convoluted tubule membrane in Kcnj10flox/flox mice, herein referred to as control mice. In contrast, low potassium intake activated Kir4.1, increased potassium currents, and hyperpolarized the distal convoluted tubule membrane. These effects of dietary potassium intake on the basolateral potassium conductance and membrane potential in the distal convoluted tubule were completely absent in inducible kidney-specific Kir4.1 knockout mice. Furthermore, high potassium intake decreased, whereas low potassium intake increased the abundance of NCC expression only in the control but not in kidney-specific Kir4.1 knockout mice. Renal clearance studies demonstrated that low potassium augmented, while high potassium diminished, hydrochlorothiazide-induced natriuresis in control mice. Disruption of Kir4.1 significantly increased basal urinary sodium excretion but it abolished the natriuretic effect of hydrochlorothiazide. Finally, hypokalemia and metabolic alkalosis in kidney-specific Kir4.1 knockout mice were exacerbated by potassium restriction and only partially corrected by a high-potassium diet. Thus, Kir4.1 plays an essential role in mediating the effect of dietary potassium intake on NCC activity and potassium homeostasis.

Published
2018

50. With no lysine kinase 4 modulates sodium potassium 2 chloride cotransporter activity in vivo

Author

Terker, Andrew S., primary, Castañeda-Bueno, Maria, additional, Ferdaus, Mohammed Z., additional, Cornelius, Ryan J., additional, Erspamer, Kayla J., additional, Su, Xiao-Tong, additional, Miller, Lauren N., additional, McCormick, James A., additional, Wang, Wen-Hui, additional, Gamba, Gerardo, additional, Yang, Chao-Ling, additional, and Ellison, David H., additional

Published
2018
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