AGE-RELATED NEPHROPATHY IN THE FISCHER-344 RAT IS ASSOCIATED WITH OVEREXPRESSION OF COLLAGENS AND COLLAGEN-BINDING HEAT-SHOCK-PROTEIN-47

To explore the possible role of heat shock protein (HSP) 47 in the age -related renal changes in Fischer 344 (F 344) rats, the expression of collagen-binding HSP47 with various proteins implicated in phenotypic modulation (alpha-smooth muscle actin, desmin, and vimentin) and fibro sis (type I, type III, and type IV collagens) was examined in young an d old F 344 rat kidneys. Male F 343 rats often develop spontaneous nep hropathy in old age. Kidneys obtained from 23-month-old F 344 rats sho wed glomerulosclerosis with marked tubulointerstitial damage including interstitial fibrosis, while no significant histological alteration w as found in the kidneys of 6-month-old rats. Immunohistochemical analy sis showed an increased accumulation of type I, type III, and type IV collagens in areas of glomerulosclerosis and interstitial fibrosis in old rat kidneys. In kidneys of young rats, collagen-binding HSP47 expr ession was weak in the glomeruli and occasionally seen in the intersti tial cells. In contrast, strong immunostaining for HSP47 was noted in the glomeruli, tubular epithelial cells, and interstitial cells in kid neys of old rats. In addition, phenotypic alterations of mesangial cel ls and interstitial cells (immunopositive for ct-smooth muscle actin), glomerular epithelial cells (immunopositive for desmin), and tubular epithelial cells (immunopositive for vimentin) were found in the kidne ys of old F 344 rats. Double immunostaining showed that all these phen otypically altered renal cells express HSP47 and that increased expres sion of HSP47 was always associated with increased expression of colla gens in the old rat kidneys. From the above observations, it is conclu ded that overexpression of HSP47 by phenotypically altered renal cells might play an important role in the excessive assembly of collagens a nd could thereby contribute to the glomerulosclerosis and interstitial fibrosis found in kidneys of aged F 344 rats.