Cisplatin-Induced Rat Renal Interstitial Fibrosis; A Possible Pathogenesis Based on the Data

Abstract

Renal interstitial fibrosis induced in F344 rats by an intraperitoneal, single dose of cisplatin (6 mg/kg body weight) was pathologically investigated. Renal tubules showing nuclear alterations and desquamation of epithelial cells were seen in the cortico-medullary junction from day 1 after dosing; these changes became more prominent on days 3 and 5. On days 7 to 13, regenerating renal epithelial cells replaced the injured epithelial cells, and the fibrosis progressed around the affected renal tubules. During the early stages (days 1-5), apoptotic epithelial cells, demonstrable by TUNEL method, appeared, and then, macrophages phagocytizing apoptotic bodies were seen in late stages (days 7-13). Macrophages and myofibroblasts (a fibrogenic cell) were significantly increased in number on days 3-5, and the numbers retained high levels by day 13. The macrophages and some renal tubular epithelial cells reacted immunohistochemically to TGF-β1, a fibrogenic factor. Macrophages were also immunoreactive to inducible nitric oxide (iNOS), and macrophages and regenerating epithelial cells showed positive reactions with histochemistry to NADPH-diaphorase, a co-enzyme of iNOS; these findings indicate that nitric oxide formed through iNOS might have participated in epithelial apoptosis, in addition to direct induction of apoptosis by cisplatin. Abnormal depositions of extracellular matrices such as collagens (types I, III and IV), fibronectin and laminin were seen in fibrotic areas and around the affected renal tubules. Based on data obtained in the present study, a possible pathogenesis of cisplatin-induced rat renal interstitial fibrosis was discussed.