TNF-α deficiency accelerates renal tubular interstitial fibrosis in the late stage of ureteral obstruction

TNF-α and TGF-β1 have a complementary relationship in fibrogenesis. This study was performed to investigate the role of TNF-α in renal tubular interstitial fibrosis. We compared the extent of renal tubular interstitial fibrosis after unilateral ureteral obstruction (UUO) between wild-type and TNF-α-deficient mice by using immunohistochemistry, enzyme-linked immunoassay, and the real-time polymerase chain reaction (PCR). In comparison with wild-type mice, there was no significant difference in the extent of renal fibrosis in the TNF-α-deficient mice at 2 weeks after UUO. By 4 weeks after UUO, however, fibrosis marked an increase in the TNF-α-deficient mice to exceed that in the wild-type mice. Immunohistochemistry, enzyme-linked immunoassay, and real-time PCR demonstrated an increase of extracellular matrix in the kidneys of TNF-α-deficient mice that was caused by upregulation of the expression of TGF-β1 and Snail, which in turn resulted from an increase of infiltrating macrophages. Real-time PCR revealed an increase in expression of the TNF-α type 2 receptor at 4 weeks after UUO, which explained the difference in the extent of renal fibrosis between TNF-α-deficient and wild-type mice. In the chronic stage of renal fibrosis, TNF-α suppresses the infiltration of macrophages by inducing TNF-α type 2 receptor expression, resulting in the amelioration of fibrosis.