title: 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 post-transplant, 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.
authors.affiliation: Department of Medicine, Division of Nephrology, Duke and Durham VA Medical Centers, Durham, North Carolina, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Orlena
authors.initials: O
authors.lastname: Cheng
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Roslyn B
authors.initials: RB
authors.lastname: Mannon
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control*; D016030:Kidney Transplantation; D051379:Mice; D008815:Mice, Inbred Strains; D010618:Phenanthrolines / Q000627:therapeutic use*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D010618:Phenanthrolines; D012333:RNA, Messenger; D011393:Procollagen-Proline Dioxygenase