The CLCA1/TMEM16A/Cl– current axis associates with H2S deficiency in diabetic kidney injury
Hak Joo Lee, … , Kumar Sharma, Balakuntalam S. Kasinath
Hak Joo Lee, … , Kumar Sharma, Balakuntalam S. Kasinath
Published January 9, 2025
Citation Information: JCI Insight. 2025;10(1):e174848. https://doi.org/10.1172/jci.insight.174848.
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Research Article Nephrology Therapeutics

The CLCA1/TMEM16A/Cl– current axis associates with H2S deficiency in diabetic kidney injury

Abstract

The role played by anionic channels in diabetic kidney disease (DKD) is not known. Chloride channel accessory 1 (CLCA1) facilitates the activity of TMEM16A (Anoctamin-1), a Ca2+-dependent Cl– channel. We examined if CLCA1/TMEM16A had a role in DKD. In mice with type 2 diabetes, renal cortical CLCA1 and TMEM16A content was increased. CLCA1 and TMEM16A content was associated with hydrogen sulfide (H2S) deficiency, mTOR complex 1 (mTORC1) activation, albuminuria, and matrix increase. Administering sodium hydrosulfide (NaHS), a source of H2S, mitigated these changes. In proximal tubular epithelial (MCT) cells, high glucose rapidly increased CLCA1 by recruiting the IL-6/STAT3 axis and augmented TMEM16A expression by stimulating its mRNA translation; these changes were abolished by NaHS. Patch clamp experiments showed that high glucose increased Cl– current in MCT cells that was ameliorated by NaHS and a TMEM16A chemical inhibitor. siRNA against CLCA1 or TMEM16A and TMEM16A inhibitor abolished high glucose–induced mTORC1 activation and matrix protein increase. Tubular expression of TMEM16A correlated with albuminuria in kidney biopsies from people with type 2 diabetes. We report a pathway for DKD in which H2S deficiency results in kidney injury by the recruitment of the CLCA1/TMEM16A/Cl– current system.

Authors

Hak Joo Lee, Yuyang Sun, Falguni Das, Wenjun Ju, Viji Nair, Christopher G. Kevil, Shankara Varadarajan, Guanshi Zhang, Goutam Ghosh Choudhury, Brij B. Singh, Matthias Kretzler, Robert G. Nelson, Kumar Sharma, Balakuntalam S. Kasinath

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Figure 1

Regulation of renal cortical CLCA1 and TMEM16A in mice with type 2 diabetes.

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Regulation of renal cortical CLCA1 and TMEM16A in mice with type 2 diabe...
(A) Renal cortical expression of CLCA1 and TMEM16A was increased in diabetic mice compared with nondiabetic controls, and it was inhibited by the administration of NaHS for 3 weeks. (B) Renal cortical H2S content was decreased in diabetic mice. (C) H2S generation was decreased in the kidney cortex of db/db diabetic mice by 45% compared with db/m control mice (0.10 ± 0.01 vs. 0.18 ± 0.01 nmol/g/min, mean ± SD, respectively, P < 0.001). (D) Blood glucose levels were not affected by NaHS. (E) Diabetes-induced increase in renal cortical content of collagen 1α2 and fibronectin was inhibited by NaHS. (F) Phosphorylation of p70 S6 kinase (P-S6K) was increased in the renal cortex of diabetic mice, indicating mTORC1 activation; it was inhibited by NaHS. (G) Diabetes-induced increase in urinary albumin-to-creatinine ratio (urinary ACR) was reduced by NaHS. Data (mean ± SD) from 9 mice in each group of mice (db/m nondiabetic controls treated with or without NaHS, db/db diabetic mice treated with or without NaHS) are shown in bars with scatterplots and were analyzed (A and D–F) by ANOVA. Data from 3 mice in each group are presented (B and C) and were analyzed by t test. *P < 0.05, **P < 0.01, ***P < 0.001. (H) Renal tubular TMEM16A expression significantly correlated with the degree of albuminuria in 49 American Indian individuals with diabetes (P = 0.0059 by ANOVA). NormALB, normo-albuminuria; microALB, micro-albuminuria; and macroALB, macroalbuminuria. (I) There was a significant correlation between TMEM16A mRNA content in the kidney tubulointerstitium and urinary albumin-to-creatinine ratio by Pearson’s correlation coefficient. (J) TMEM16A expression in the human kidneys of control (n = 3) and diabetes individuals (n = 4).