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

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.