Exosomal lncRNA TUG1 derived from human urine-derived stem cells attenuates renal ischemia/reperfusion injury by interacting with SRSF1 to regulate ASCL4-mediated ferroptosis

• DOI: 10.1186/s13287-022-02986-x
• Publication Date: 2022-07-15T10:04:24Z
• Authors: Zejia Sun; Jiyue Wu; Qing Bi; Wei Wang
• Keywords: Medicine (General); Taurine; Urine-derived stem cells; Ischemia/reperfusion injury; QD415-436; Exosomes; Kidney; Biochemistry; Mice; 03 medical and health sciences; R5-920; Ischemia; Animals; Ferroptosis; Humans; Hypoxia; 0303 health sciences; LncRNA TUG1; Serine-Arginine Splicing Factors; Research; Stem Cells; Acute Kidney Injury; Acute kidney injury; Mice, Inbred C57BL; Reperfusion Injury; RNA, Long Noncoding

AbstractBackgroundHuman urine-derived stem cells (USCs)-derived exosomes (USC-Exo) could improve kidney ischemia/reperfusion injury (IRI), while the underlying mechanisms of this protective effect remain unclear.MethodsHuman USCs and USC-Exo were isolated and verified by morphology and specific biomarkers. The effects of USC-Exo on ferroptosis and kidney injury were detected in the IRI-induced acute kidney injury (AKI) model in C57BL/6 mice. The effects of USC-Exo on ferroptosis and lncRNA taurine-upregulated gene 1 (TUG1) were detected in hypoxia/reoxygenation (H/R)-treated human proximal tubular epithelial cells (HK-2). The interaction of SRSF1 and TUG1, ACSL4 was checked via RNA pull-down/RIP and RNA stability assays. The effects of LncRNA TUG1 on SRSF1/ACSL4-mediated ferroptosis were verified in H/R-treated HK-2 cells and the IRI-induced AKI mouse models.ResultsUSC-Exo treatment improved kidney injury and ameliorated ferroptosis in IRI-induced AKI mouse models. USC-Exo were rich in lncRNA TUG1, which suppressed ferroptosis in HK-2 cells exposed to H/R. Mechanistically, lncRNA TUG1 regulates the stability of ACSL4 mRNA by interacting with RNA-binding protein SRSF1. In addition, SRSF1 upregulation or ACSL4 downregulation partially reversed the protective effect of lncRNA TUG1 on ferroptosis in H/R-treated HK-2 cells. Further, ACSL4 upregulation partially reversed TUG1’s repression on kidney injury and ferroptosis in IRI-induced AKI mice.ConclusionCollectively, lncRNA TUG1 carried by USC-Exo regulated ASCL4-mediated ferroptosis by interacting with SRSF1 and then protected IRI-induced AKI. Potentially, USC-Exo rich in lncRNA TUG1 can serve as a promising therapeutic method for IRI-AKI.