甲状旁腺激素（PTH）的肾脏作用促进1,25-维生素D的产生。然而，控制PTH相关的维生素D活化的信号机制仍未知晓。在这里，我们证明盐诱导激酶（SIKs）在PTH信号转导下协调肾脏1,25-维生素D的产生。PTH通过cAMP依赖性PKA磷酸化来抑制SIK的细胞活性。组织和单个细胞转录组学显示，PTH和药理学上的SIK抑制剂都可以调节近端小管的维生素D基因模块。SIK抑制剂可以增加小鼠和人类胚胎干细胞来源的肾脏器官oids的1,25-维生素D产生和肾Cyp27b1 mRNA表达。全局和肾脏特异性Sik2 / Sik3突变体小鼠显示Cyp27b1上调，血清1,25-维生素D升高，同时无需PTH即可发生高钙血症。SIK底物CRTC2显示PTH和SIK抑制剂可诱导其与肾脏中关键的Cyp27b1调节增强子结合，这些增强子在活体内也需要SIK抑制剂来增加Cyp27b1。最后，在肾病矿物质骨病（CKD-MBD）的足细胞损伤模型中，SIK抑制剂治疗刺激了肾Cyp27b1表达和1,25-维生素D产生。所有这些结果表明，肾脏中的PTH / SIK / CRTC信号轴控制Cyp27b1的表达和1,25-维生素D的合成。这些发现表明，SIK抑制剂可能有助于刺激CKD-MBD中的1,25-维生素D产生。

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. Lastly, 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 to stimulate 1,25-vitamin D production in CKD-MBD.