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)

2

D

3

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)

2

D

3

through histone modifications at their promoter regions in a genetic hypercalciuric stone-forming (GHS) rat model.