Human Umbilical Cord Mesenchymal Stem Cells Protect against Renal Ischemia-Reperfusion Injury by Secreting Extracellular Vesicles Loaded with miR-148b-3p That Target Pyruvate Dehydrogenase Kinase 4 to Inhibit Endoplasmic Reticulum Stress at the Reperfusion Stages

Abstract

Renal ischemia-reperfusion (I/R) injury is a leading cause of acute kidney injury (AKI), with high mortality. Recent studies have reported that human umbilical cord mesenchymal stem cells (HucMSCs) play an important role in repairing organ and tissue injuries because of their unique characteristics. However, the potential of HucMSC extracellular vesicles (HucMSC-EVs) to promote the repair of renal tubular cells remains to be explored. This study found that HucMSC-EVs derived from HucMSCs played a protective role and were associated with kidney I/R injury. We found that miR-148b-3p in HucMSC-EVs had a protective effect against kidney I/R injury. HK-2 cells overexpressing miR-148b-3p were protected against I/R injury by inhibiting apoptosis. Next, the target mRNA of miR-148b-3p was predicted online, and the target mRNA, pyruvate dehydrogenase kinase 4 (PDK4), was identified and verified using dual luciferase. We discovered that I/R injury significantly increased endoplasmic reticulum (ER) stress, whereas siR-PDK4 inhibited these effects and protected against I/R injury. Interestingly, after administrating HucMSC-EVs to HK-2 cells, PDK4 expression and ER stress induced by I/R injury were significantly inhibited. HK-2 ingested miR-148b-3p from HucMSC-EVs, and its ER induced by I/R injury was significantly deregulated. This study suggests that HucMSC-EVs protect kidneys from I/R injury during the early I/R stage. These results suggest a new mechanism for HucMSC-EVs in treating AKI and provide a new treatment strategy for I/R injury.

Keywords

• human umbilical cord mesenchymal stem cells
• apoptosis
• extracellular vesicles
• ischemia/reperfusion injury
• endoplasmic reticulum stress
• MicroRNA