Inhibition of prolyl-4-hydroxylase ameliorates chronic rejection of mouse kidney allografts

Abstract

Interstitial fibrosis, glomerulosclerosis and arteriosclerosis are the major components of chronic allograft nephropathy (CAN), the leading cause of late graft failure after transplantation. To investigate the mechanism of collagen deposition in CAN, we studied the effects of prolyl-hydroxylase inhibitor (PHI), an enzyme essential for collagen formation, using a mouse model of kidney transplantation. Kidneys from H-2b mice were transplanted into MHC-incompatible H-2d recipients (allografts) and at 3 weeks posttransplant, received either PHI or vehicle treatment daily for 3 weeks. At 6 weeks post-transplant, GFR was significantly improved in the allografts receiving PHI (3.3±0.5 mL/min/kg) compared with those receiving vehicle (1.8±0.5 mL/min/kg, p<0.05), while renal function was relatively unimpaired in the nonrejecting isografts (6.45±0.53 mL/min/kg). Allografts had histologic changes of CAN but the severity was significantly reduced with PHI treatment compared with vehicle, with reductions in interstitial inflammation and fibrosis. Furthermore, TGFâ and connective tissue growth factor mRNA expression was enhanced in both allograft groups compared with the isografts. In conclusion, PHI-treated allografts had improved renal function and reduced the severity of renal injury as a result of CAN. Inhibition of matrix synthesis may be a useful adjunct in ameliorating the development of CAN in humans.