The effect of antioxidant on development of fibrosis by cisplatin in rats.
Cisplatin causes chronic interstitial disease with fibrosis, but the development mechanism of interstitial fibrosis is not yet understood. We examined the effect of an antioxidant, N,N'-diphenyl-1,4-phenylenediamine (DPPD), on development of interstitial fibrosis induced by cisplatin. Cisplatin increased blood urea nitrogen (BUN), plasma creatinine, and elicited glucosuria and enzymuria at 3 days after administration, but these changes were restored to the normal level after 14 days. Type III collagen increased from 7 days after administration of cisplatin and the expansion of the interstitial fibrosis area became evident at 14 days. Sustained renal fibrosis worsened renal function again at 56 days. Administration of DPPD, which was started at 3 days after cisplatin treatment, significantly inhibited the increase in renal type III collagen contents and the expansion of the interstitial fibrosis area without affecting enzymuria and increased BUN. These results indicate that anti-fibrotic action of DPPD is not secondary due to the inhibition of acute renal injury but is rather a direct effect on renal fibrogenesis. DPPD did not prevent the infiltration of macrophages by cisplatin, suggesting that anti-fibrotic action of DPPD was not mediated by the inhibition of inflammatory cellular influx. It is suggested that reactive oxygen species are involved in cisplatin-induced renal interstitial fibrosis.
Kawai
Yoshiko
Y
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan. kawai@gly.oups.ac.jp
Satoh
Tomohiko
T
Hibi
Daisuke
D
Ohno
Yukihiro
Y
Kohda
Yuka
Y
Miura
Katsuyuki
K
Gemba
Munekazu
M
D000199:Actins / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D024061:Collagen Type III / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007677:Kidney Function Tests; D008297:Male; D010655:Phenylenediamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000199:Actins; D000447:Aldehydes; D000975:Antioxidants; D002945:Cisplatin; D024061:Collagen Type III; D010655:Phenylenediamines; C498862:Acta2 protein, rat; C004845:N,N'-diphenyl-4-phenylenediamine; C027576:4-hydroxy-2-nonenal