A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis

  • J Clin Invest. 2023 May 1;133(9):e163627. doi: 10.1172/JCI163627.
Sung-Hee Yoon  1 ,  Mark B Meyer  2 ,  Carlos Arevalo  3 ,  Murat Tekguc  4 ,  Chengcheng Zhang  4 ,  Jialiang S Wang  1 ,  Christian D Castro Andrade  1 ,  Katelyn Strauss  1 ,  Tadatoshi Sato  1 ,  Nancy A Benkusky  2 ,  Seong Min Lee  2 ,  Rebecca Berdeaux  5 ,  Marc Foretz  6 ,  Thomas B Sundberg  3 ,  Ramnik J Xavier  3  7 ,  Charles H Adelmann  8 ,  Daniel J Brooks  1 ,  Anthony Anselmo  9 ,  Ruslan I Sadreyev  9  10 ,  Ivy A Rosales  10 ,  David E Fisher  8 ,  Navin Gupta  4 ,  Ryuji Morizane  4  11 ,  Anna Greka  3 ,  J Wesley Pike  12 ,  Michael Mannstadt  1  3 ,  Marc N Wein  1  3  11
Affiliations
  • 1. Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 2. Department of Nutritional Sciences, University of Wisconsin - Madison, Madison, Wisconsin, USA.
  • 3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • 4. Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 5. Department of Integrative Biology and Pharmacology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • 6. Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.
  • 7. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • 8. Cutaneous Biology Research Center, Department of Dermatology.
  • 9. Department of Molecular Biology, and.
  • 10. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 11. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
  • 12. Department of Biochemistry, University of Wisconsin - Madison, Madison, Wisconsin, USA.
PMID: 36862513 DOI: 10.1172/JCI163627
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; Calcium; G protein–coupled receptors; Nephrology; Protein kinases.
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