LncRNA TMC3-AS1 silence alleviates lipopolysaccharide-induced acute kidney injury by suppressing Wnt5a-mediated autophagy and pyroptosis pathway.

Abstract

Long non-coding RNA TMC3-AS1 is identified to be upregulated by lipopolysaccharide (LPS) in inflammatory disease, but its role in acute kidney injury (AKI) is almost unknown. The study investigated the involvement of TMC3-AS1 in LPS-induced AKI and its downstream molecular regulatory mechanism. Our data suggested that knocking down TMC3-AS1 significantly reduced renal dysfunction, tissue inflammation and tissue damage in LPS-induced mice, and promoted cell viability, inhibited inflammation, apoptosis and necrosis in LPS-stimulated human renal tubular epithelial cells HK2. Meanwhile, silencing TMC3-AS1 decreased the expression levels of Wnt5a, Atg5, NLRP3 and cleaved caspase1 and the ratio of LC3II/LC3I, but elevated p62 level in vivo and in vitro, suggesting the inhibitory effect of TMC3-AS1 silence on Wnt5a signaling, autophagy, and pyroptosis. Mechanically, TMC3-AS1 upregulated the expression of WNT5A mRNA and Wnt5a protein through competitively binding with miR-148a-3p, thus elevating the expression levels of autophagy and pyroptosis-associated markers in LPS-induced HK2 cells. MiR-148a-3p mimic also exerted protective effects on LPS-treated HK2 cells, which was counteracted by overexpressing WNT5A or TMC3-AS1. Altogether, these findings reveal that TMC3-AS1 inhibition restrains LPS-triggered AKI progression through inactivating Wnt5a -mediated autophagy and pyroptosis pathway.