Abstract
Previous studies have demonstrated the importance of TSLP-TSLPR in inflammatory, allergic, and fibrotic diseases. However, their exact molecular mechanism in regulating renal fibrosis has not been fully explored yet. The current study identified the high expression levels of TSLP and TSLPR in human and mouse hydronephrotic tissues. In addition, immunofluorescence staining showed that TSLP was highly expressed in renal tubular cells, while TSLPR was mainly co-localized with α-SMA, a marker of fibroblasts. Knocking out TSLPR in the UUO model could alleviate the severity of renal fibrosis. Most importantly, the application of antibody blockade of TSLP reduced the fibrotic level in the UUO model. The functional analysis revealed that the hypoxic exposure could induce the overexpression of TSLP in renal tubular cells via HIF-1α. The tubular cell-derived TSLP could bind to the TSLPR of fibroblasts in a paracrine manner to activate them. Specifically, the HIF-1α/TSLP/TSLPR-axis could activate fibroblasts through the STAT3 signaling pathway. This study revealed a mechanistic interaction of HIF-1α/TSLP/TSLPR and STAT3 signaling pathways in the activation and proliferation of human and murine kidney fibroblasts; these pathways might be exploited as a therapeutic target in renal fibrosis.