Age-related nephropathy in the Fischer 344 rat is associated with overexpression of collagens and collagen-binding heat shock protein 47

Abstract

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 fibrosis (type I, type III, and type IV collagens) was examined in young and old F 344 rat kidneys. Male F 344 rats often develop spontaneous nephropathy in old age. Kidneys obtained from 24-month-old F 344 rats showed glomerulosclerosis with marked tubulointerstitial damage including interstitial fibrosis, while no significant histological alteration was found in the kidneys of 6-month-old rats. Immunohistochemical analysis 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 expression was weak in the glomeruli and occasionally seen in the interstitial cells. In contrast, strong immunostaining for HSP47 was noted in the glomeruli, tubular epithelial cells, and interstitial cells in kidneys of old rats. In addition, phenotypic alterations of mesangial cells and interstitial cells (immunopositive for alpha-smooth muscle actin), glomerular epithelial cells (immunopositive for desmin), and tubular epithelial cells (immunopositive for vimentin) were found in the kidneys of old F 344 rats. Double immunostaining showed that all these phenotypically altered renal cells express HSP47 and that increased expression of HSP47 was always associated with increased expression of collagens in the old rat kidneys. From the above observations, it is concluded that overexpression of HSP47 by phenotypically altered renal cells might play an important role in the excessive assembly of collagens and could thereby contribute to the glomerulosclerosis and interstitial fibrosis found in kidneys of aged F 344 rats.

Coexpression of Collagens and Collagen-Binding Heat Shock Protein 47 in Human Diabetic Nephropathy and IgA Nephropathy

“…For example, the HSP47 expression was augmented in CCl 4 -induced liver cirrhosis, bleomycin-induced pulmonary fibrosis and antithymocyte serum induced glomerulosclerosis in rats in parallel with increased deposition of various collagens [12, 16, 22]. The expression of HSP47 was also markedly elevated in gentamicin nephropathy, hypertensive Dahl rat kidneys, cisplatin-induced tubulointerstitial nephritis and aging Fischer 344 rat kidneys in parallel with increased expression of various collagens [13, 23, 24, 25]. From the collagen-synthesizing ability, it is thought that increased levels of HSP47 in human DN and IgAN might have a key regulatory role for sclerotic/fibrotic changes that are found in the advanced stage of the disease.…”

“…This was performed to localize HSP47/CD68, HSP47/α-smooth muscle actin, HSP47/type III collagen and HSP47/type IV collagen in the same renal section as described earlier [12, 13]. Briefly, selected paraffin sections (4 µm) were deparaffinized, treated with 0.3% hydrogen peroxide in methanol (30 min), reacted with 10% nonimmune goat serum (10 min) and incubated with monoclonal antibody against HSP47 for 1 h. The sections were further treated with biotinylated second antibody (10 min) and streptavidin-alkaline phosphatase (10 min) and developed with BCIP/NBT which produce a dark-purple stain.…”

Aging in the Canine Kidney

“…64 Research in rodents has provided further support for the roles of insulin-like growth factor 1 and heat shock proteins. 62,85 GS in humans was associated with upregulation of cell-cycle regulators p16…”

Heat Shock Protein 47 in Renal Scarring

“…Earlier studies have convincingly shown that increased synthesis of collagens by interstitial myofibroblasts and tubular epithelial cells results in tubulointerstitial fibrosis. In rat models, an increased expression of HSP47 was consistently observed in the interstitial myofibroblasts and tubular epithelial cells during the process of experimental and spontaneous tubulointerstitial fibrosis [14, 15, 16]. Increased expression of HSP47 was seen in and around areas of interstitial fibrosis, and it colocalizes with collagens (types I and III).…”