Cobalt Protoporphyrin Attenuates Rat Obstructive Nephropathy: Role of Cellular Infiltration

Abstract Objectives Renal interstitial inflammation is closely related to the progressive renal fibrosis. It has been reported that heme oxygenase-1 (HO-1) induction attenuated renal fibrosis in obstructive nephropathy. To elucidate the antifibrogenic mechanisms of HO-1, we examined the effect of HO-1 induction on renal interstitial inflammation. Methods Adult male rats underwent unilateral ureteral obstruction (UUO). The rats were pretreated with cobalt protoporphyrin (CoPP, a potent HO-1 inducer; 15 or 50 mg/kg) subcutaneously on the day −6 and −1 before UUO. Sham-operated rats served as controls. Renal interstitial fibrosis, macrophage and T cell infiltration were immunohistochemically assessed on the day 5 after UUO. Gene expressions of HO-1 and profibrogenic molecules were determined by real-time reverse transcriptase-polymerase chain reaction. Results CoPP dose-dependently induced HO-1 activity, protein, and messenger RNA (mRNA) expression in the renal cortices. CoPP significantly attenuated the renal fibrosis in a dose-dependent manner. Gene expressions of transforming growth factor-beta and extracellular matrix proteins were upregulated in UUO and were attenuated by CoPP. CoPP markedly inhibited T cell infiltration. Unexpectedly, it enhanced macrophage influx dose dependently. Double immunostaining of macrophage and HO-1 showed that CoPP elicited HO-1 overexpression in infiltrating macrophages, whereas UUO alone did not. Conclusions HO-1 induction protected against the renal interstitial fibrosis in rat obstructive nephropathy. It is suggested that inhibition of T cell influx is, at least in part, involved in the protection. Increased macrophages that overexpress HO-1 may play an important role in attenuating renal fibrosis.