Immunohistochemical Study of Rat Renal Interstitial Fibrosis Induced by Repeated Injection of Cisplatin, with Special Reference to the Kinetics of Macrophages and Myofibroblasts

Abstract

Progressive renal interstitial fibrosis occurs following tissue injury, resulting in chronic renal failure. In the fibrogenesis, macrophages are speculated to induce myofibroblasts producing matrix protein. The kinetics of these cells in renal fibrosis induced in rats by repeated injection of cisplatin (CDDP) (2 mg/kg body weight, once weekly) was investigated immunohistochemically. During the 10-wk injection period, epithelial damage of the proximal renal tubules in the corticomedullary junction was seen, followed by cystic dilation of the affected tubules. During the 8-wk recovery period following the seventh injection, the size of the dilated lumina was diminished and atrophic tubules lined by regenerating epithelial cells appeared. Morphometrical analysis revealed that fibrosis began to develop around the dilated renal tubules in the injection period and was more advanced in the following recovery period. Coinciding with development of fibrotic tissues, the number of alpha-smooth muscle actin-positive myofibroblasts was significantly increased in the areas compared to that of controls. In the injection period, despite a significant increase in myofibroblast number, an elevation of ED-1 (primary antibody)-positive macrophage number was not observed. In the recovery period, however, a significant elevation of macrophage number was noticed in markedly advanced interstitial fibrosis. This suggests that rapid expansion of the macrophage population, probably resulting from release from myelosuppression due to CDDP, might contribute in part to development of myofibroblasts, leading to the augmented fibrosis in the recovery period.

Immunohistochemical Analysis of Macrophages, Myofibroblasts, and Transforming Growth Factor-β Localization during Rat Renal Interstitial Fibrosis Following Long-Term Unilateral Ureteral Obstruction

“…The fine structures closely resembled those reported previously in obstructed rabbit kidneys (21). These cells were regarded as myofibroblasts (21,39,43 small number of EDl-positive cells were detected in the medulla and papilla of the obstructed kidneys (Fig. 10).…”

“…The fibrotic lesion is evoked through complex pathologic processes, requiring participation of various inflammatory cells and abnormal accumulation of extracellular matrices (ECM) (5,7,9,19,35,39). To clarify the pathogenesis, nephrotoxic chemicals such as puromycin aminonucleoside (4,6,7), adriamycin (28), cyclosporine (45), and cisdiamminedichloroplatinum (cisplatin) (39,43) have been used to chemically induce renal interstitial fibrosis in rats.…”

Heterogeneity of Macrophage Populations and Myofibroblasts Appearing in Rat Renal Interstitial Fibrosis

“…, an anticancer drug with nephrotoxicity, can induce renal interstitial fibrosis in rats [5][6][7] . The initial lesion by cisplatin is tubular damage of the lower straight part (P 3 segment) of the proximal tubule in the corticomedullary junction.…”

“…Fibrotic areas begin to develop around the affected tubules on day 7 and subsequent days, leading to progressive renal interstitial fibrosis. Chronic renal fibrosis (chronic model) can be induced in rats by intraperitoneal injections (2 mg/kg body weight) of cisplatin once weekly for 6 or 7 weeks 5,6 . After the cessation of repeated injection, interstitial fibrosis progressively develops around the affected tubules in the corticomedullary junction; particularly, at 5 and 7 weeks after the cessation, the treated rats show the greatest lesion of renal interstitial fibrosis (Fig.…”

“…The renal fibrosis has greater im pact on the progression of ren al disease t han glomerulosclerosis 3,4 . The renal fibrosis is characterized by appearance of various inflammatory cells, development of myofibroblasts, and abnormal accumulation of extracellular matrices (ECMs) [4][5][6][7][8] . In the last decade, there have been significant advances in cellular and molecular pathology, which have contributed to understanding of the roles of cells and factors responsible for the development of renal fibrosis.…”