ADSCs-EVs Carrying circITCH Inhibit Pyroptosis of Renal Tubular Epithelial Cells and Alleviate LPS-Induced Acute Kidney Injury

This study investigates the mechanism of adipose-derived stem cells-extracellular vesicles (ADSCs-EVs) carrying circITCH in lipopolysaccharides (LPS)-induced acute kidney injury (AKI). The effect of EVs on Pyroptosis was validated in vitro and in vivo LPS-induced models. circITCH, RBM15, or CRBN expression was detected via RT-qPCR or western blot. The binding of circITCH to HuR or β-TrCP was analyzed by RIP or RNA pull down. The interaction between HuR, β-TrCP, and RBM15 was analyzed by Co-IP or RIP. After treatment with cycloheximide or MG132, HuR protein expression or ubiquitination level was detected by western blot. m6A modification and of IGF2BP1 enrichment on CRBN were analyzed by RIP. EVs treatment decreases Cre and BUN levels, reduces renal tubular injury score and injured renal tubules, and inhibits Pyroptosis in renal tissues and cells. EVs carry circITCH into cells to upregulate circITCH expression in renal tissues and cells. Mechanistically, low expression of circITCH weakens the interaction between HuR and β-TrCP, reduces HuR ubiquitination, and enhances the interaction between HuR and RBM15 mRNA, thereby increasing m6A modification on CRBN and promoting CRBN expression in an IGF2BP1-dependent manner. Collectively, ADSCs-EVs alleviate renal tubular epithelial cell Pyroptosis by carrying circITCH, ultimately reducing LPS-induced AKI.

RBM15; acute kidney injury; adipose‐derived stem cells; circITCH; extracellular vesicles.