{"doi":"10.1681/asn.2021030392","title":"Gentamicin Inhibits Ca2+ Channel TRPV5 and Induces Calciuresis Independent of the Calcium-Sensing Receptor–Claudin-14 Pathway","abstract":"Background Treatment with the aminoglycoside antibiotic gentamicin can be associated with severe adverse effects, including renal Ca 2+ wasting. The underlying mechanism is unknown but it has been proposed to involve activation of the Ca 2+ -sensing receptor (CaSR) in the thick ascending limb, which would increase expression of claudin-14 (CLDN14) and limit Ca 2+ reabsorption. However, no direct evidence for this hypothesis has been presented. Methods We studied the effect of gentamicin in vivo using mouse models with impaired Ca 2+ reabsorption in the proximal tubule and the thick ascending limb. We used a Cldn14 promoter luciferase reporter assay to study CaSR activation and investigated the effect of gentamicin on activity of the distal nephron Ca 2+ channel transient receptor potential vanilloid 5 (TRPV5), as determined by patch clamp in HEK293 cells. Results Gentamicin increased urinary Ca 2+ excretion in wild-type mice after acute and chronic administration. This calciuretic effect was unaltered in mice with genetic CaSR overactivation and was present in furosemide-treated animals, whereas the calciuretic effect in Cldn14−/− mice and mice with impaired proximal tubular Ca 2+ reabsorption (claudin-2 [CLDN2]-deficient Cldn2−/− mice) was equivalent to that of wild-type mice. In vitro , gentamicin failed to activate the CaSR. In contrast, patch clamp analysis revealed that gentamicin strongly inhibited rabbit and human TRPV5 activity and chronic gentamicin administration downregulated distal nephron Ca 2+ transporters. Conclusions Gentamicin does not cause hypercalciuria via activation of the CaSR-CLDN14 pathway or by interfering with proximal tubular CLDN2-dependent Ca 2+ reabsorption. Instead, gentamicin blocks distal Ca 2+ reabsorption by direct inhibition of the Ca 2+ channel TRPV5. These findings offer new insights into Ca 2+ wasting in patients treated with gentamicin.","journal":"Journal of the American Society of Nephrology","year":2022,"id":249648,"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":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":275287,"name":"Megan R. Beggs","orcid":"0000-0002-2690-1785","position":1,"is_corresponding":false},{"id":513917,"name":"Sung-Wan An","orcid":null,"position":2,"is_corresponding":false},{"id":890450,"name":"Patrícia G. Ferreira","orcid":"0000-0002-6132-1356","position":3,"is_corresponding":false},{"id":875624,"name":"Justin J. Lee","orcid":null,"position":4,"is_corresponding":false},{"id":891028,"name":"Matthias T. Wolf","orcid":null,"position":5,"is_corresponding":false},{"id":275291,"name":"R. Todd Alexander","orcid":"0000-0001-7396-7894","position":6,"is_corresponding":false},{"id":890451,"name":"Henrik Dimke","orcid":"0000-0002-9170-2168","position":7,"is_corresponding":false},{"id":891027,"name":"Wouter H. van Megen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T00:24:23.754337Z","pmid":"35022312","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":[]}