Faculty, Staff and Student Publications
Language
English
Publication Date
5-1-2023
Journal
The Journal of Clinical Investigation
DOI
10.1172/JCI163627
PMID
36862513
PMCID
PMC10145948
PubMedCentral® Posted Date
May 2023
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Bone Biology, Nephrology, Calcium, G protein–coupled receptors, Protein kinases
Published Open-Access
yes
Recommended Citation
Yoon, Sung-Hee; Meyer, Mark B; Arevalo, Carlos; et al., "A Parathyroid Hormone/Salt-Inducible Kinase Signaling Axis Controls Renal Vitamin D Activation and Organismal Calcium Homeostasis" (2023). Faculty, Staff and Student Publications. 1232.
https://digitalcommons.library.tmc.edu/uthmed_docs/1232