Activation of vitamin D receptor by the Wilms' tumor gene product mediatesapoptosis of renal cells

The Wilms' tumor transcription factor WT1 is required for kidney developmen t, but little is known about WT1 downstream signaling in renal cells. This study reported an approximately fivefold upregulation of vitamin D receptor (VDR) mRNA and protein in human embryonic kidney (KEK) 293 cells that stab ly expressed WT1 at a level comparable to the developing kidney in vivo. Co -transfection of HEK 293 cells with expression plasmids encoding four diffe rent WT1 splicing variants stimulated mouse vdr promoter activity more than fourfold. A 201-bp fragment was identified in the proximal vdr promoter th at was required for transactivation by WT1. This critical sequence containe d a predicted WT1 con-sensus site, which bound to recombinant WT1 protein. Temporal changes of vdr and wt1 mRNA levels in developing rat kidneys were correlated closely. The active metabolite 1,25-dihydroxyvitamin D-3 (1,25-( OH)(2)D-3) strongly inhibited the proliferation of wt1-transfected HEK 293 cells. Exposure to 1,25-(OH)(2)D-3 caused apoptosis of cultured wt1 immunop ositive cells from mouse embryonic kidney cortex. These findings suggest th at transcriptional activation of the VDR by WT1 can mediate programmed deat h of renal embryonic cells in response to 1,25(OH)(2)D-3. The results provi de the first evidence for a role of the vitamin D endocrine system in renal cell growth and differentiation during development.