Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of clinical investigation, 2023-05, Vol.133 (9), p.1-17

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.