Prevention of chronic allograft nephropathy with vitamin D

Chronic allograft nephropathy ( CAN) is the leading cause of late allograft loss in kidney transplantation. Interstitial fibrosis and glomerulosclerosis are characteristic of CAN. Transforming growth factor beta- 1 ( TGF beta- 1) is associated with both of these histologic findings in the transplant setting. Recent studies have suggested that vitamin D signaling pathways may interact with and regulate TGFb- 1 mediated events. We examined the efficacy of 1,25- dihydroxyvitamin D-3, the active metabolite of vitamin D [ 1,25-( OH) D-2(3)], the active metabolite of vitamin D, as monotherapy to prolong allograft survival and preserve renal function in a rat model of CAN, the Fisher 344 to Lewis model. Recipients went without treatment or were treated with cyclosporine A ( CSA; 10 days) or 1,25( OH) 2D3 ( 1000, 500 or 250 ng/ kg/ day). Grafts were harvested at the time of rejection or at 24 weeks post- transplant. A portion of the graft was processed for histology and immunohistochemistry and a second portion was analyzed for protein expression by western blotting. Not only did 1,25-( OH) D-2(3) treatment significantly prolong graft survival, but it also prevented histological changes associated with CAN. 1,25-( OH) D-2(3) treatment significantly decreased Smad 2 expression. This TGF beta signaling molecule is likely involved in fibrosis. Moreover, 1,25-( OH) D-2(3) treatment increased Smad 7 expression, an important feedback molecule in the TGFb- 1 signaling pathway. This suggests that 1,25( OH) 2D3 interacts with TGFb- 1 in limiting histological injury in this model of CAN. Furthermore, 1,25-( OH) D-2(3), treatment increased expression of matrix metalloproteinase 2 ( MMP- 2), thus directly affecting levels of another important matrix molecule. Taken together our data suggests that 1,25-( OH) D-2(3) mitigates CAN in this model by altering TGFb- 1 and matrix- regulating molecules.