Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is important for dendritic cell (DC) in migrating, recognizing, capturing, presenting antigens and in initiating T cell responses. In the present study, we investigated the role of DC-SIGN in renal tubulointerstitial inflammation and fibrosis. DC-SIGN was mainly expressed in tubular epithelial cells and DC-SIGN+ DCs were primarily distributed in renal tubulointerstitial areas during the early stage of nephritis, which was correlated with the degree of renal tubular interstitial lesions and fibrosis. In vitro, DC-SIGN expression in cultured human renal tubular epithelial cells was elevated when treated by tumor necrosis factor-alpha, and was inhibited by anti-P-selectin lectin-EGF domain monoclonal antibody (PsL-EGFmAb). In a rat model of chronic renal interstitial fibrosis, there was a significant correlation of DC-SIGN expression with DC-SIGN+ DC distribution and the degree of tubulointerstitial lesion. PsL-EGFmAb reduced DC-SIGN expression and DC-SIGN+ DC accumulation in renal tissues in this rat model. These results suggest that DC-SIGN plays an important role in DC-mediated renal tubular interstitial lesions induced by immuno-inflammatory responses.