Peritransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection

Abstract

Summary 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. × 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 dependant, 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.

Influence of Heme Oxygenase-1 on Microcirculation After Kidney Transplantation

“…Carbon monoxide directly induces its vasorelaxation effects via activation of both smooth muscle soluble guanylate cyclase and high conductance potassium channels. The smooth muscle cell derived carbon monoxide also has a paracrine effect on endothelial cells by inhibiting the production of endothelin-1 [30,31]. Additionally, we observed a hyperperfusion of the peritubular arterioles and capillaries after preconditioning with a significantly higher flow compared with the non-preconditioned grafts and control groups, although a vasodilation occurred.…”

The Heme Oxygenase System Suppresses Perirenal Visceral Adiposity, Abates Renal Inflammation and Ameliorates Diabetic Nephropathy in Zucker Diabetic Fatty Rats

“…Moreover, the elevated collagen deposition in untreated ZDFs was associated with increased expression of fibronectin, another extracellular matrix protein that together with collagen are known to deplete nephrin causing proteinuria and renal insufficiency [19]–[22], [56]. Given that previous studies have reported increased HO-1 expression in the interstitium and tubular epithelium of the cortex following the administration of HO-inducers [60], [74], and incidentally the interstitium and tubular epithelium were among the areas with significant lesion in untreated ZDF, the present study and previous reports in literature strongly suggest that the HO system alleviates not only tubulo-interstitial injury, but also suppress perivascular and glomerular fibrosis to improve renal function.…”

Effects of Losartan, HO-1 Inducers or HO-1 Inhibitors on Erectile Signaling in Diabetic Rats

“… Group 3: STZ‐induced diabetic rats (diabetic untreated control group). Group 4: received losartan as Angiotensin converting enzyme (ACE) inhibitor (10 mg/kg IP, 3 times/ week for 2 weeks) [28]. Group 5: received cobalt protoporphyrin (CoPP) as HO inducer (0.5 mg/100 gm IP, 3 times/week for 2 weeks) [29]. Group 6: received both losartan and CoPP. Group 7: received losartan and HO inhibitor; stannus mesoporphyrin (SnMP, 50 µmol/kg single IP injection dissolved in 0.1 M NaOH) [26]. …”

“…Group 5: received cobalt protoporphyrin (CoPP) as HO inducer (0.5 mg/100 gm IP, 3 times/week for 2 weeks) [29].…”