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Cisplatin is an effective antitumor drug, but nephrotoxicity has restricted its clinical use. Renal interstitial fibrosis is a major complication of cisplatin treatment, due to the increased accumulation of extracellular matrix (ECM) proteins. Ets-1 protein plays a role in matrix remodeling by regulating matrix-degrading enzymes. We studied the role of Ets-1, matrix metalloproteinase-1 (MMP-1), and interstitial collagen (type III) in experimental cisplatin nephropathy. Wistar rats ( n = 24) were treated with cisplatin (6 mg/kg), and killed on days 3, 7, and 14, along with control rats. By immunohistochemistry, a significant increase ( P < 0.02) in the number of Ets-1-positive cells (40.09 +/- 1.52) was detected in kidneys of cisplatin-treated rats on day 3, compared with the number in control rat kidneys (29.80 +/- 0.13). The number of Ets-1-positive cells decreased in kidneys from cisplatin-treated rats on days 7 (10.93 +/- 1.20) and 14 (12.16 +/- 0.60). The expression of MMP-1 showed a similar pattern, increasing on day 3, but decreasing on days 7 and 14. The decreased levels of Ets-1 and MMP-1 were associated with increased interstitial accumulation of collagen in kidneys of cisplatin-treated rats on day 14. Molecular interactions among Ets-1, MMP-1, and type III collagens might play a role in matrix remodeling in cisplatin nephropathy.

The molecular mechanisms of fibrosis in radiation nephropathy have received scant attention. Heat shock protein 47 (HSP47), a collagen-binding stress protein, helps in the intracellular processing of procollagen molecules during collagen synthesis. We investigated the role of HSP47 in the progression of radiation nephropathy using experimental radiation nephropathy. Experimental rat groups were as follows: (i) group I, sham operated (n = 12); (ii) group II, single doses of irradiation, either 7, 15 or 25 Gy to left kidney (n = 60); and (iii) group III, a similar irradiation procedure as group II after right nephrectomy (n = 60). The rats were followed up until 9 months after renal exposure to radiation. Renal dysfunction (as determined by serum creatinine and blood urea nitrogen) and hypertension were noted in group III rats, along with inflammatory cell infiltration and interstitial fibrosis (as determined by increased deposition of collagens). Compared to control rat kidneys, an increased expression of HSP47 was noted in kidneys obtained from irradiated rats. By double immunostaining, HSP47-expressing cells were identified as α-smooth muscle actin-positive myofibroblasts and vimentin-positive tubular epithelial cells. Increased expression of HSP47 was closely associated with increased deposition of collagens in the widened interstitium of irradiated rats. Overexpression of HSP47 by phenotypically altered tubulointerstitial cells might play a role in excessive assembly/synthesis of collagens and could contribute to tubulointerstitial fibrosis in radiation nephropathy. [ABSTRACT FROM AUTHOR]