A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis
Sung-Hee Yoon, … , Michael Mannstadt, Marc N. Wein
Sung-Hee Yoon, … , Michael Mannstadt, Marc N. Wein
Published March 2, 2023
Citation Information: J Clin Invest. 2023;133(9):e163627. https://doi.org/10.1172/JCI163627.
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Research Article Bone biology Nephrology

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.

Authors

Sung-Hee Yoon, Mark B. Meyer, Carlos Arevalo, Murat Tekguc, Chengcheng Zhang, Jialiang S. Wang, Christian D. Castro Andrade, Katelyn Strauss, Tadatoshi Sato, Nancy A. Benkusky, Seong Min Lee, Rebecca Berdeaux, Marc Foretz, Thomas B. Sundberg, Ramnik J. Xavier, Charles H. Adelmann, Daniel J. Brooks, Anthony Anselmo, Ruslan I. Sadreyev, Ivy A. Rosales, David E. Fisher, Navin Gupta, Ryuji Morizane, Anna Greka, J. Wesley Pike, Michael Mannstadt, Marc N. Wein

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Figure 4

Global/inducible deletion of all 3 SIK isoforms causes PTH-independent hypercalcemia and lethality.

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Global/inducible deletion of all 3 SIK isoforms causes PTH-independent h...
(A) 6-week-old mice of the indicated genotypes were treated with tamoxifen. Body weights of male and female inducible SIK triple-KO (iTKO) mice were obtained at the time of sacrifice. (B) Blood urea nitrogen (BUN) measurement in control and iTKO mice. (C) Renal histology (H&E stain) from control and iTKO animals revealing no obvious differences between genotypes. Scale bars: 250 μm. (D) Alkaline phosphatase (ALP) and 1,25-vitamin D measurement in control and iTKO mice. (E and F) Renal gene expression of Cyp27b1, Cyp24a1, and Trpv5 by RT-qPCR. (G) Serum analysis of calcium, PTH, and phosphorus in control and iTKO mice. (H) TRAP staining of decalcified, paraffin-embedded tibia sections reveals increased osteoclasts in iTKO mice. Osteoclasts are essentially absent following OPG-Fc treatment. Scale bars: 500 μm. (I) Survival curve of iTKO mice treated with or without OPG-Fc (200 μg/mouse) (n = 42 Ctrl, n = 14 iTKO, n = 13 iTKO + OPG-Fc). Data are shown as the mean ± SD, and each dot represents an individual mouse. Student’s t test was performed for statistical analysis, and P values are shown.