Streptozotocin-induced diabetic nephropathy in rats: The role of inflammatory cytokines

The role of inflammatory cytokines in the pathogenesis of diabetic nephropathy has been studied in streptozotocin-induced diabetic rats. Rat kidneys were examined by light and electron microscopy and kidney homogenates were also analyzed by Western blot and flow cytometry for the expression of markers of inflammation namely, CD4+ and CD8+ T cells, macrophages, MHC classes I and 11, the proinflammatory cytokines tumor necrosis factor-alpha, interferon-gamma and nitric oxide (NO). Light and electron microscope examination revealed infiltration of mononuclear cells throughout the renal parenchyma, with the glomeruli being more severely affected especially at 8 months after disease induction. Western blot and flow cytometric analyses revealed the infiltrating cells to be CD4+ T cells, CD8+ T cells and macrophages. Western blot analyses also revealed increased expression of the proinflammatory and Th1 cytokines tumor necrosis factor-alpha, interferon-gamma as well as nitric oxide. Using flow cytometry, we have shown that the difference in expression of CD4+ T cells in control and diabetic kidneys is more significant at I month than at 8 months, while expression of CD8+ T cells is more significant at 8 months. We speculate therefore that diabetic nephropathy is probably initiated and driven by a Th1 process. CD8+ T cells, however, become more significant at later stages of the disease when tissue loss is evident. Since NO induction also occurs only after 8 months, we hypothesize that NO might be significant for the later stages of the disease. Our data implicate inflammation in the pathogenesis of diabetic nephropathy in view of the overexpression of the proinflammatory cytokines TNF-alpha and IFN-gamma and the cells that secrete them in the early and late phases of the disease. (c) 2005 Elsevier Ltd. All rights reserved.