To address the effect of bone-related factors and 1,25(OH)₂D₃/vitamin D receptor (VDR) on renal stone formation in idiopathic hypercalciuria using genetic hypercalciuric rats.

The basal levels of bone-related factors were detected in Sprague-Dawley and genetic hypercalciuric rats. In VDR silenced kidneys, the expression levels of bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (Runx2), Osterix, and osteopontin (OPN) were measured, respectively. Tubular calcium phosphate deposits in kidneys and renal tubular epithelial cells (RTECs) were assessed using von Kossa stain. Kidneys were stained with immunohistochemical staining for OPN expression. Gene and protein expression levels of BMP2, Runx2, and Osterix were examined in RTECs incubated with 1,25(OH)₂D₃.

The basal levels of BMP2, Runx2, Osterix, and OPN were significantly increased in genetic hypercalciuric rats, whereas there were no differences in the expression levels of msh homeobox homolog 2 and alkaline phosphatase between the genetic hypercalciuric and normal control rats. VDR knockdown in genetic hypercalciuric rats reduced the expression levels of BMP2, Runx2, Osterix, and OPN. Tubular calcium phosphate deposits were also decreased in VDR silenced kidneys. Immunohistochemical staining showed that there was a reduction in OPN expression in RTECs along with reduction in calcification. Gene and protein expression levels of BMP2, Runx2, and Osterix were upregulated in RTECs incubated with 1,25(OH)₂D₃. The calcium phosphate deposits in RTECs were also increased by elevated 1,25(OH)₂D₃.

Our findings indicate that BMP2, Runx2, Osterix, and OPN might play an important role in renal stone formation in idiopathic hypercalciuria, and 1,25(OH)₂D₃/VDR might be the significant regulator in this process.