{"doi":"10.1016/j.kint.2021.06.030","title":"Specific disruption of calcineurin-signaling in the distal convoluted tubule impacts the transcriptome and proteome, and causes hypomagnesemia and metabolic acidosis","abstract":"Adverse effects of calcineurin inhibitors (CNI), such as hypertension, hyperkalemia, acidosis, hypomagnesemia and hypercalciuria, have been linked to dysfunction of the distal convoluted tubule (DCT). To test this, we generated a mouse model with an inducible DCT-specific deletion of the calcineurin regulatory subunit B alpha (CnB1-KO). Three weeks after CnB1 deletion, these mice exhibited hypomagnesemia and acidosis, but no hypertension, hyperkalemia or hypercalciuria. Consistent with the hypomagnesemia, CnB1-KO mice showed a downregulation of proteins implicated in DCT magnesium transport, including TRPM6, CNNM2, SLC41A3 and parvalbumin but expression of calcium channel TRPV5 in the kidney was unchanged. The abundance of the chloride/bicarbonate exchanger pendrin was increased, likely explaining the acidosis. Plasma aldosterone levels, kidney renin expression, abundance of phosphorylated sodium chloride-cotransporter and abundance of the epithelial sodium channel were similar in control and CnB1-KO mice, consistent with a normal sodium balance. Long-term potassium homeostasis was maintained in CnB1-KO mice, but in-vivo and ex-vivo experiments indicated that CnB1 contributes to acute regulation of potassium balance and sodium chloride-cotransporter. Tacrolimus treatment of control and CnB1-KO mice demonstrated that CNI-related hypomagnesemia is linked to impaired calcineurin-signaling in DCT, while hypocalciuria and hyponatremia occur independently of CnB1 in DCT. Transcriptome and proteome analyses of isolated DCTs demonstrated that CnB1 deletion impacts the expression of several DCT-specific proteins and signaling pathways. Thus, our data support a critical role of calcineurin for DCT function and provide novel insights into the pathophysiology of CNI side effects and involved molecular players in the DCT.","journal":"Kidney International","year":2021,"id":172677,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":709036,"name":"Viktória Fisi","orcid":"0000-0001-7183-0800","position":1,"is_corresponding":false},{"id":709560,"name":"Sandra Moser","orcid":null,"position":2,"is_corresponding":false},{"id":709561,"name":"Agnieszka Wengi","orcid":null,"position":3,"is_corresponding":false},{"id":709562,"name":"Monique Carrel","orcid":null,"position":4,"is_corresponding":false},{"id":709563,"name":"Dominique Loffing‐Cueni","orcid":null,"position":5,"is_corresponding":false},{"id":709037,"name":"David Pentón","orcid":"0000-0002-6425-3766","position":6,"is_corresponding":false},{"id":709564,"name":"Denise V. Kratschmar","orcid":null,"position":7,"is_corresponding":false},{"id":709038,"name":"Ludovica Rizzo","orcid":"0000-0002-0319-722X","position":8,"is_corresponding":false},{"id":399414,"name":"Soeren S. Lienkamp","orcid":"0000-0003-2963-6865","position":9,"is_corresponding":false},{"id":431993,"name":"Alex Odermatt","orcid":"0000-0002-6820-2712","position":10,"is_corresponding":false},{"id":434709,"name":"Markus M. Rinschen","orcid":"0000-0002-9252-1342","position":11,"is_corresponding":false},{"id":685413,"name":"Johannes Loffing","orcid":"0000-0002-9415-6588","position":12,"is_corresponding":false},{"id":709559,"name":"Eszter Banki","orcid":null,"position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-18T23:46:41.424716Z","pmid":"34252449","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":[]}