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Introduction Vitamin D plays a critical role in bone and mineral metabolism and also controls other physiologic and pathophysiologic processes, including skeletal muscle function, reproductive health, cancer risk and progression, [...], 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.

CYP24A1 is a multifunctional, P450 mitochondrial enzyme that catabolizes the vitamin D hormone (calcitriol, 1,25(OH)2D3), its precursor (calcifediol, 25(OH)D3), and numerous vitamin D metabolites. In the kidney, Cyp24a1 is induced by 1,25(OH)2D3 and fibroblast growth factor 23 (FGF23) and potently suppressed by PTH to control the circulating levels of 1,25(OH)2D3. Cyp24a1 is controlled by a pair of promoter proximal (PRO) vitamin D response elements (VDREs) that are aided by distal, downstream (DS) enhancers. The downstream 1 region of Cyp24a1 (DS1) enhancer is kidney-specific and responsible for PTH and FGF23 actions, and the downstream 2 region of Cyp24a1 enhancer responds to 1,25(OH)2D3 in all tissues. Despite this knowledge, in vivo contributions of the PRO VDREs to basal expression, FGF23 activation, and PTH suppression of Cyp24a1 remain unknown. In this study, we selectively mutated the PRO VDREs in the mouse to address these questions. We found mutation of the VDREs leads to a dramatic loss of VDR occupancy, a reduction of 1,25(OH)D3-induced kidney Cyp24a1 expression, and near elimination of intestinal Cyp24a1 induction. FGF23 induction of Cyp24a1 was reduced but not eliminated and still showed a synergistic increase with 1,25(OH)2D3. PTH suppression of Cyp24a1 was unchanged, despite minor reductions in total for phosphorylated cAMP-response element binding protein occupancy. Finally, VDR recruitment was dramatically reduced across the DS enhancers in the Cyp24a1 locus. Taken together, our data suggest a cooperative relationship between the DS and PRO enhancers in the regulation of Cyp24a1 by 1,25(OH)2D3 and FGF23 and points to the DS1 region as a crucial basal switch for Cyp24a1 activity that further defines the interconnected genomic control in vitamin D catabolism. [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of the prostate, associated with lower urinary tract symptoms (LUTSs). Taraxaci Herba (TH), commonly known as dandelion, has traditionally been utilized in East Asia to treat symptoms related to LUTSs. Based on this traditional use, our study aimed to explore the inhibitory effects of TH on BPH progression using a testosterone propionate-induced rat model. To induce BPH, male Sprague Dawley rats were castrated and injected subcutaneously with testosterone propionate (3 mg/kg/day) for 28 days. Concurrently, TH extract was administered orally at doses of 100 and 300 mg/kg/day throughout the four-week period of testosterone propionate injections. The TH extract significantly reduced both the absolute and relative weights of the prostate, along with histopathological changes in the gland. Moreover, it lowered serum levels of testosterone and dihydrotestosterone and reduced the expression of the androgen receptor in the prostate. Additionally, the TH extract modulated the protein expressions of Bax and Bcl-2, which are key regulators of apoptosis in prostate cells. Collectively, our findings suggest that TH inhibits BPH development partially by modulating androgen signaling and inducing apoptosis within the prostate. [ABSTRACT FROM AUTHOR]

Introduction In the early 1970s, 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]] was identified as both the exclusive, metabolically active form of vitamin D and a key component of what proved to be an [...], The vitamin D receptor (VDR) is the single known regulatory mediator of hormonal 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]] in higher vertebrates. It acts in the nucleus of vitamin D target cells to regulate the expression of genes whose products control diverse, cell type-specific biological functions that include mineral homeostasis. In this Review we describe progress that has been made in defining new cellular sites of action of this receptor, the mechanisms through which this mediator controls the expression of genes, the biology that ensues, and the translational impact of this receptor on human health and disease. We conclude with a brief discussion of what comes next in understanding vitamin D biology and the mechanisms that underlie its actions.