title: Peritransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection.
abstract: Allogen-independent injury contributes to chronic rejection in renal allografts and heme oxygenase-1 (HO-1) has been shown to be protective in a number of settings. This study evaluated the effect of renal allograft recipient HO-1 up-regulation on chronic rejection in a rat model. Rat (F344 to Lewis) renal transplantation recipients were grouped: (i) cyclosporine (CsA) alone (0.75 mg/kg s.c. x 10 day; n = 5); (ii) CsA + low dose cobalt protoporphyrin (CoPP) an HO-1 inducer (0.5 mg/kg i.p. on days -5,0,5; n = 13) and (iii) CsA + high dose CoPP (5.0 mg/kg i.p. on days -5,0,5; n = 8). Renal function was assessed by serum creatinine levels on day 140. Histopathologic changes in allografts were graded. Morphometric analyses performed to objectively quantify the vascular changes and glomerulosclerosis. HO-1 expression quantified by Western blot and both HO-1 and endothelin (ET-1) localized using immunohistochemistry. Recipients treated with CsA + high dose CoPP had significantly decreased cortical scarring, vascular hyalinization and intimal thickness. They also had a significant, dose-dependent, reduction in luminal obliteration and glomerulosclerosis by morphometric analyses. This freedom from chronic rejection in recipients treated with CoPP translated into quiescent grafts at postoperative day 140 with immunostaining and Western blot demonstrating decreased level of HO-1 versus controls (P = 0.012). In summary, the peritransplant up-regulation of HO-1 in renal allograft recipients significantly attenuates chronic rejection in rat renal allografts by inhibiting transplant vasculopathy.
authors.affiliation: The Department of Surgery, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Eric L R
authors.initials: EL
authors.lastname: Bédard
authors.forename: Jifu
authors.initials: J
authors.lastname: Jiang
authors.forename: Neil
authors.initials: N
authors.lastname: Parry
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Peter
authors.initials: P
authors.lastname: Kim
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Roland
authors.initials: R
authors.lastname: Buelow
authors.forename: Robert
authors.initials: R
authors.lastname: Zhong
mesh_terms: D000818:Animals; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use; D004790:Enzyme Induction; D006084:Graft Rejection / Q000517:prevention & control*; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D011524:Protoporphyrins / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
chemical_list: D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D016572:Cyclosporine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1