The Effect of Antioxidant on Development of Fibrosis by Cisplatin in Rats

Abstract

Abstract. 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.

Effect of Antioxidants and Mesenchymal Stem Cells on Cisplatin Induced Renal Fibrosis in Rats

“…Both of them had been carefully assessed and scored in our study. In line with some other reports [35,16], significant reduction has been found in both stem cell and antioxidant groups than in the cisplatin group and this was further proved and fortified via immunohistochemical assay of α-SMA and Ki-67 in renal tissue. Both α-SMA and Ki-67 contents were significantly lower in renal tissue denoting decreased myelofibrosis, collagen formation and cell proliferation in the stem cell group and antioxidant group more than cisplatin group.…”

“…Where serum creatinine and BUN showed significant decrease in the stem cells and antioxidant groups in comparison to the cisplatin group as was also reported previously by other studies [33,16]. Tubular injury and interstitial fibrosis are cardinal features of cisplatin induced nephrotoxicity on histopathological evaluation [34].…”

“…Tubulointerstetial fibrosis is a directly related to cisplatin administration via the increased expression of reactive oxygen specie's and the increased free radicals especially raised malondialdehyde levels as was previously reported [16,31,32].…”

“…At day14 after cisplatin or saline administration, blood samples were obtained and kidneys were removed [16].…”

Regeneration of Injured Renal Tubules

“…Oxidative stress activates transcription of inflammatory mediators, including NF-kB and cyclooxygenase-2 (COX-2). Antioxidant treatment can ameliorate cisplatin-induced acute renal injury and fibrosis (15,18). The anti-inflammatory and renal protective effects of COX-2 inhibitor on cisplatininduced AKI are accompanied by inhibition of NADPH oxidase and MAPKs, suggesting that feed-forward deteriorating processes between oxidative stress and inflammation are involved in cisplatin nephrotoxicity (17).…”