Inhibition of PRMT1 alleviates sepsis-induced acute kidney injury in mice by blocking the TGF-1 and IL-6 trans-signaling pathways

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)-beta 1/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-beta 1/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-beta 1 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-beta 1-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-beta 1/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.