{"doi":"10.1152/ajprenal.00284.2020","title":"Distal convoluted tubule Cl<sup>−</sup>concentration is modulated via K<sup>+</sup>channels and transporters","abstract":"Cl − -sensitive with-no-lysine kinase (WNK) plays a key role in regulating the thiazide-sensitive Na + -Cl − cotransporter (NCC) in the distal convoluted tubule (DCT). Cl − enters DCT cells through NCC and leaves the cell across the basolateral membrane via the Cl − channel ClC-K2 or K + -Cl − cotransporter (KCC). While KCC is electroneutral, Cl − exit via ClC-K2 is electrogenic. Therefore, an alteration in DCT basolateral K + channel activity is expected to influence Cl − movement across the basolateral membrane. Although a role for intracellular Cl − in the regulation of WNK and NCC has been established, intracellular Cl − concentrations ([Cl − ] i ) have not been directly measured in the mammalian DCT. Therefore, to measure [Cl − ] i in DCT cells, we generated a transgenic mouse model expressing an optogenetic kidney-specific Cl-Sensor and measured Cl − fluorescent imaging in the isolated DCT. Basal measurements indicated that the mean [Cl − ] i was ~7 mM. Stimulation of Cl − exit with low-Cl − hypotonic solutions decreased [Cl − ] i , whereas inhibition of KCC by DIOA or inhibition of ClC-K2 by NPPB increased [Cl − ] i , suggesting roles for both KCC and ClC-K2 in the modulation of [Cl − ] i . Blockade of basolateral K + channels (Kir4.1/5.1) with barium significantly increased [Cl − ] i . Finally, a decrease in extracellular K + concentration transiently decreased [Cl − ] i , whereas raising extracellular K + transiently increased [Cl − ] i , further suggesting a role for Kir4.1/5.1 in the regulation of [Cl − ] i . We conclude that the alteration in ClC-K2, KCC, and Kir4.1/5.1 activity influences [Cl − ] i in the DCT.","journal":"American Journal of Physiology-Renal Physiology","year":2020,"id":61765,"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":55,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":326408,"name":"Nathan J. Klett","orcid":"0000-0002-7102-1728","position":1,"is_corresponding":false},{"id":326409,"name":"Avika Sharma","orcid":"0000-0002-7979-0820","position":2,"is_corresponding":false},{"id":258937,"name":"Charles N. Allen","orcid":"0000-0002-3689-2878","position":3,"is_corresponding":false},{"id":327702,"name":"Wen-Hui Wang","orcid":null,"position":4,"is_corresponding":false},{"id":327703,"name":"Chao-Ling Yang","orcid":null,"position":5,"is_corresponding":false},{"id":278310,"name":"David H. Ellison","orcid":"0000-0003-2915-265X","position":6,"is_corresponding":false},{"id":326407,"name":"Xiao‐Tong Su","orcid":"0000-0001-8121-8105","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-18T21:09:47.114172Z","pmid":"32715757","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":[]}