Suppression of TRPM2 reduces renal fibrosis and inflammation through blocking TGF-β1-regulated JNK activation.

Chronic kidney disease (CKD) is a major cause of death. Renal fibrosis and inflammation are common pathways contributing to the development of this disease. However, the molecular mechanisms underlying CKD are not fully understood. TRPM2 (Transient receptor potential melastatin-2) was previously identified as a potential target in various diseases due to its multiple functions. In the study, mice with unilateral urethral obstruction (UUO) were used to explore the effects of TRPM2 on renal injury. First, TRPM2 expression was up-regulated in kidney of mice after UUO. Renal histological analysis using H&E and PAS staining showed that histological changes induced by UUO were markedly alleviated in TRPM2-deficient mice. In addition, TRPM2 knockout markedly improved renal dysfunction, as evidenced by the reduced serum creatine, blood urea nitrogen (BUN), kidney injury molecule 1 (KIM-1) expression and enhanced Nephrin levels. TRPM2 ablation significantly attenuated renal interstitial fibrosis in mice with UUO via decreasing transforming growth factor (TGF)-β1 expression, accompanied with the reduction of fibrotic genes, such as α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin (FN) and Collagen 1 alpha 1 (Col1α1). Suppressing TRPM2 expression also suppressed inflammatory cell infiltration and release of pro-inflammatory factors in UUO-triggered renal fibrosis. Further, TRPM2 deficiency inhibited IκBα/nuclear factor (NF)-κB signaling in UUO-treated mice. Moreover, c-Jun N-terminal kinase (JNK) signaling was blocked by TRPM2 knockout in UUO mice. Surprisingly, the in vitro results indicated that blocking JNK activation resulted in the suppression of TGF-β1-induced fibrosis and inflammation. Together, these findings demonstrate that the inhibition of TRPM2 might protect against renal fibrosis and inflammation through impeding JNK activation regulated by TGF-β1.

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