Inhibition of PRMT1 alleviates sepsis‐induced acute kidney injury in mice by blocking the TGF‐β1 and IL‐6 trans‐signaling pathways

Abstract

Sepsis‐induced acute kidney injury (SI‐AKI) causes renal dysfunction and has a high mortality rate. Protein arginine methyltransferase‐1 (PRMT1) is a key regulator of renal insufficiency. In the present study, we explored the potential involvement of PRMT1 in SI‐AKI. A murine model of SI‐AKI was induced by cecal ligation and perforation. The expression and localization of PRMT1 and molecules involved in the transforming growth factor (TGF)‐β1/Smad3 and interleukin (IL)‐6/signal transducer and activator of transcription 3 (STAT3) signaling pathways were detected in mouse kidney tissues by western blot analysis, immunofluorescence, and immunohistochemistry. The association of PRMT1 with downstream molecules of the TGF‐β1/Smad3 and IL‐6/STAT3 signaling pathways was further verified in vitro in mouse renal tubular epithelial cells. Cecal ligation and perforation caused epithelial–mesenchymal transition, apoptosis, and inflammation in renal tissues, and this was alleviated by inhibition of PRMT1. Inhibition of PRMT1 in SI‐AKI mice decreased the expression of TGF‐β1 and phosphorylation of Smad3 in the renal cortex, and downregulated the expression of soluble IL‐6R and phosphorylation of STAT3 in the medulla. Knockdown of PRMT1 in mouse renal tubular epithelial cells restricted the expression of Cox‐2, E‐cadherin, Pro‐caspase3, and phosphorylated Smad3 (involved in the TGF‐β1‐mediated signaling pathway), and also blocked IL‐6/soluble IL‐6R, inducing the expression of Cox‐2 and phosphorylated‐STAT3. In conclusion, our findings suggest that inhibition of PRMT1 mitigates SI‐AKI by inactivating the TGF‐β1/Smad3 pathway in the cortex and the IL‐6/STAT3 pathway in the medulla. Our findings may aid in the identification of potential therapeutic target molecules for SI‐AKI.