Cobalt protoporphyrin attenuates rat obstructive nephropathy: role of cellular infiltration.
OBJECTIVE
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.
Iwai
Tomoaki
T
Department of Urology, Osaka City University Medical School, Osaka, Japan.
Kitamoto
Kouichirou
K
Teramoto
Kae
K
Machida
Yuichi
Y
Tamada
Satoshi
S
Yukimura
Tokihito
T
Iwao
Hiroshi
H
Nakatani
Tatsuya
T
Miura
Katsuyuki
K
D000818:Animals; D005355:Fibrosis / Q000150:complications / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014517:Ureteral Obstruction / Q000209:etiology / Q000517:prevention & control*
D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat