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Article Dans Une Revue The Journal of clinical investigation Année : 2023

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

Sung-Hee Yoon
  • Fonction : Auteur
Mark Meyer
Carlos Arevalo
  • Fonction : Auteur
Murat Tekguc
Jialiang Wang
Christian Castro Andrade
  • Fonction : Auteur
Katelyn Strauss
  • Fonction : Auteur
Tadatoshi Sato
  • Fonction : Auteur
Nancy Benkusky
  • Fonction : Auteur
Seong Min Lee
Rebecca Berdeaux
Marc Foretz
  • Fonction : Auteur
Thomas Sundberg
Charles Adelmann
Daniel Brooks
Anthony Anselmo
  • Fonction : Auteur
Ivy Rosales
David Fisher
  • Fonction : Auteur
Navin Gupta
  • Fonction : Auteur
Ryuji Morizane
Anna Greka
J. Wesley Pike
  • Fonction : Auteur
Michael Mannstadt
Marc Wein

Résumé

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.
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Dates et versions

hal-04300970 , version 1 (23-11-2023)

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Sung-Hee Yoon, Mark Meyer, Carlos Arevalo, Murat Tekguc, Chengcheng Zhang, et al.. A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis. The Journal of clinical investigation, 2023, 133 (9), pp.101661. ⟨10.1172/JCI163627⟩. ⟨hal-04300970⟩

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