{"doi":"10.1172/jci.insight.174848","title":"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.","journal":"JCI Insight","year":2025,"id":549940,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":518135,"name":"Yuyang Sun","orcid":"0000-0002-2256-0581","position":1,"is_corresponding":false},{"id":1370154,"name":"Falguni Das","orcid":null,"position":2,"is_corresponding":false},{"id":5964,"name":"Wenjun Ju","orcid":"0000-0002-9136-8454","position":3,"is_corresponding":false},{"id":29419,"name":"Viji Nair","orcid":"0000-0003-1657-954X","position":4,"is_corresponding":false},{"id":226777,"name":"Christopher G. Kevil","orcid":"0000-0003-0863-7260","position":5,"is_corresponding":false},{"id":1445334,"name":"Shankara Varadarajan","orcid":null,"position":6,"is_corresponding":false},{"id":321342,"name":"Guanshi Zhang","orcid":"0000-0001-6557-4521","position":7,"is_corresponding":false},{"id":716583,"name":"Goutam Ghosh Choudhury","orcid":"0000-0003-0101-5821","position":8,"is_corresponding":false},{"id":342725,"name":"Brij B. Singh","orcid":"0000-0003-0535-5997","position":9,"is_corresponding":false},{"id":5968,"name":"Matthias Kretzler","orcid":"0000-0003-4064-0582","position":10,"is_corresponding":false},{"id":68431,"name":"Robert G. Nelson","orcid":"0000-0001-7307-3786","position":11,"is_corresponding":false},{"id":292969,"name":"Kumar Sharma","orcid":"0000-0002-7550-8525","position":12,"is_corresponding":false},{"id":340026,"name":"Balakuntalam S. Kasinath","orcid":"0000-0002-6360-101X","position":13,"is_corresponding":false},{"id":716580,"name":"Hak Joo Lee","orcid":"0000-0003-3954-3216","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T02:54:12.321988Z","pmid":"39782685","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}