Participation of Different Macrophage Populations and Myofibroblastic Cells in Chronically Developed Renal Interstitial Fibrosis after Cisplatin-induced Renal Injury in Rats

Abstract

Abstract. To shed some light on the mechanisms behind renal fibrogenesis, the present study immunohistochemically investigated the participation of different macrophage populations and myofibroblastic cells in rat renal interstitial fibrosis developed chronically after repeated injection of cisplatin (2 mg/kg body weight, once weekly for 7 weeks). During the 19-week recovery period after the final injection, fibrotic lesions progressively developed in the corticomedullary junction, with the greatest level at post-final injection (FPI) week 5, and then the lesions were gradually repaired by PFI week 19, indicative of a healing process. In conformity with the development of fibrotic lesions, the number of myofibroblastic cells reacting with an anti-␣-smooth muscle actin antibody was increased, with a peak at PFI week 3, and collagens (types I, III, and IV), fibronection, and laminin were excessively accumulated in these areas. Interstitial cells forming the fibrotic lesions showed mitotic activity at the early stages, whereas they disappeared by apoptosis in the healing process. A large number of cells reacting with an antibody of ED1 (for exudate macrophages), ED2 (for resident macrophages), or OX6 (for major histocompatibility complex class II-presenting macrophages and interstitial dendritic cells) had already appeared at PF1 week 1, and then their numbers increased, with a peak at PFI weeks 7, 3, and 9 in ED1-, ED2-, and OX6-positive cells, respectively. Thereafter, the number of ED1-and ED2-positive cells decreased, whereas the number of OX6-positive cells persisted at a high level until PFI week 19. In the healing process, clusters of lymphocytes were present, the development of which might have been related to OX6-positive cells. The present study demonstrated that chronically developing rat renal interstitial fibrosis might be produced by the complicated mechanisms evoked by interactions between different macrophage populations and myofibroblastic cells, because macrophages show heterogeneous functions depending on microenvironmental factors.

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

“…ED1-positive cells may be responsible for production of TNF-α and TGF-β1 in the early stages, leading to the induction of myofibroblastic cells 25,56 . In fact, α-SMApositive myofibroblastic cell number begins to increase with increased number of ED1-positive cells in the acute and chronic models 6,25,26 . ED2 is used to detect resident macrophages 17,27,30,34 .…”

“…In the chronic model 6 , a large number of ED1-, ED2-and OX6-positive cells appear at 1-3 weeks after the cessation of repeated injection. ED1-and ED2-positive cell numbers peak at 3 to 7 weeks, and thereafter gradually decrease.…”

“…, 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.…”