{"doi":"10.1172/jci163627","title":"A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis","abstract":"The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.","journal":"Journal of Clinical Investigation","year":2023,"id":323256,"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":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9584,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":348013,"name":"Mark B. Meyer","orcid":"0000-0001-6612-7491","position":1,"is_corresponding":false},{"id":15643,"name":"Carlos Arevalo","orcid":"0000-0003-2492-2547","position":2,"is_corresponding":false},{"id":863435,"name":"Murat Tekgüç","orcid":"0000-0001-7570-5898","position":3,"is_corresponding":false},{"id":1038002,"name":"Chengcheng Zhang","orcid":"0000-0002-0550-107X","position":4,"is_corresponding":false},{"id":289941,"name":"Jialiang S. Wang","orcid":"0000-0002-3409-7619","position":5,"is_corresponding":false},{"id":289940,"name":"Christian Castro","orcid":"0000-0003-3054-2831","position":6,"is_corresponding":false},{"id":1038591,"name":"Katelyn Strauss","orcid":null,"position":7,"is_corresponding":false},{"id":290640,"name":"Tadatoshi Sato","orcid":null,"position":8,"is_corresponding":false},{"id":368282,"name":"Nancy A. Benkusky","orcid":null,"position":9,"is_corresponding":false},{"id":367601,"name":"Seong Min Lee","orcid":"0000-0001-5017-5456","position":10,"is_corresponding":false},{"id":719241,"name":"Rebecca Berdeaux","orcid":"0000-0002-9929-1711","position":11,"is_corresponding":false},{"id":467351,"name":"Marc Foretz","orcid":"0000-0001-7017-9032","position":12,"is_corresponding":false},{"id":1038003,"name":"Thomas B. Sundberg","orcid":"0000-0001-8967-8480","position":13,"is_corresponding":false},{"id":104389,"name":"Ramnik J. Xavier","orcid":"0000-0002-5630-5167","position":14,"is_corresponding":false},{"id":429785,"name":"Charles H. Adelmann","orcid":"0000-0001-7823-4374","position":15,"is_corresponding":false},{"id":289943,"name":"Daniel J. Brooks","orcid":"0000-0001-7408-9851","position":16,"is_corresponding":false},{"id":668438,"name":"Anthony Anselmo","orcid":"0000-0002-4761-1541","position":17,"is_corresponding":false},{"id":260528,"name":"Ruslan I. Sadreyev","orcid":"0000-0002-4240-5466","position":18,"is_corresponding":false},{"id":364575,"name":"Ivy A. Rosales","orcid":"0000-0003-0621-3202","position":19,"is_corresponding":false},{"id":69344,"name":"David E. Fisher","orcid":"0000-0002-5506-0575","position":20,"is_corresponding":false},{"id":754421,"name":"Navin Gupta","orcid":"0000-0001-6445-3496","position":21,"is_corresponding":false},{"id":630569,"name":"Ryuji Morizane","orcid":"0000-0002-0377-5667","position":22,"is_corresponding":false},{"id":2281,"name":"Anna Greka","orcid":"0000-0001-5697-7791","position":23,"is_corresponding":false},{"id":367600,"name":"J. Wesley Pike","orcid":"0000-0001-9356-7281","position":24,"is_corresponding":false},{"id":43073,"name":"Michael Mannstadt","orcid":"0000-0003-0867-9778","position":25,"is_corresponding":false},{"id":268753,"name":"Marc N. Wein","orcid":"0000-0002-6015-8147","position":26,"is_corresponding":false},{"id":380733,"name":"Sung-Hee Yoon","orcid":"0000-0002-3500-607X","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T01:07:52.377944Z","pmid":"36862513","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":[]}