Human idiopathic hypercalciuria (IH) is the most common cause of calcium oxalate nephrolithiasis with perturbed calcium metabolism with increased bone resorption and decreased renal calcium reabsorption, which can be phenotype-copied in the genetic hypercalciuric stone-forming (GHS) rat model. We previously demonstrated that high VDR expression plays important roles in the development of hypercalciuria in the GHS rats. However, the underlying mechanism through which VDR impact hypercalciuria development remains to be fully understood. Here, we sought to determine how VDR regulated its target genes that are implicated in calcium homeostasis and potentially hypercalciuria. We found that VDR expression in the GHS rats was elevated in the calcium transporting tissues, as well as in the thymus and prostate, but not in lung, brain, heart, liver and spleen, when compared with control SD rats. Snail expression in the GHS rats was significantly downregulated in kidney, intestine, thymus and testis. Intraperitoneal injection of 1,25(OH)₂D₃ significantly upregulated the expression of renal calcium sensing receptor (CaSR), intestinal calcium transporters transient receptor potential vanilloid type 6 (TRPV6), and VDR in GHS rats, compared with that in control SD rats. ChIP assays revealed that VDR specifically bound to the proximal promoters of target genes, followed by histone H3 hyperacetylation or hypermethylation. Collectively, our results suggest that elevated VDR expression may contribute to the development of hypercalciuria by sensitizing VDR target genes to 1,25(OH)₂D₃ through histone modifications at their promoter regions in a genetic hypercalciuric stone-forming (GHS) rat model.

人类特发性高钙尿症 (IH) 是草酸钙肾结石的最常见原因，其钙代谢紊乱，骨吸收增加，肾钙重吸收减少，这可以在遗传性高钙尿结石形成 (GHS) 大鼠模型中进行表型复制。我们之前证明了高 VDR 表达在 GHS 大鼠高钙尿症的发展中起重要作用。然而，VDR 影响高钙尿症发展的潜在机制仍有待充分了解。在这里，我们试图确定 VDR 如何调节其与钙稳态和潜在高钙尿症有关的靶基因。我们发现 GHS 大鼠中的 VDR 表达在钙转运组织以及胸腺和前列腺中升高，但在肺、脑、心脏、与对照 SD 大鼠相比，肝脏和脾脏。GHS 大鼠的 Snail 表达在肾、肠、胸腺和睾丸中显着下调。腹腔注射 1,25(OH)与对照组 SD 大鼠相比，₂ D _{3显着上调 GHS 大鼠肾钙敏感受体 (CaSR)、肠钙转运蛋白瞬时受体电位香草素 6 型 (TRPV6) 和 VDR 的表达。}ChIP 分析显示 VDR 特异性结合靶基因的近端启动子，然后是组蛋白 H3 高乙酰化或高甲基化。总之，我们的研究结果表明，在遗传性高钙尿结石形成 (GHS) 大鼠模型中，通过在其启动子区域的组蛋白修饰使 VDR 靶基因对 1,25(OH) ₂ D ₃敏感，升高的 VDR 表达可能有助于高钙尿症的发生。.