The CLCA1/TMEM16A/Cl- Current Axis Associates with H2S Deficiency in Diabetic Kidney Injury

Overview

Journal JCI Insight

Date 2025 Jan 9

PMID 39782685

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

Affiliations

Soon will be listed here.

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.

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