HucMSC exosomes-delivered 14-3-3 zeta enhanced autophagy via modulation of ATG16L in preventing cisplatin-induced acute kidney injury

The clinical application of cisplatin is restricted by its side effects of nephrotoxicity. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-ex) have an important effect in tissue injury repair. Our previous work discovered that pretreatment with human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-ex) alleviated cisplatin-induced acute kidney injury (AKI) by activating autophagy both in vitro and in vivo. In this study, we further explored the mechanisms of hucMSC-ex in autophagy for preventing cisplatin-induced nephrotoxicity. We discovered that 14-3-3 zeta was contained in hucMSC-ex, and knockdown and overexpression 14-3-3 zeta reduced and enhanced the autophagic activity respectively. Furthermore, Knockdown of 14-3-3 zeta alleviated the preventive effect of hucMSC-ex. In contrast, overexpression of 14-3-3 zeta enhanced the effect. Further results confirmed that hucMSC-ex increased ATG16L expression and that 14-3-3 zeta interacted with ATG16L, promoting the localization of ATG16L at autophagosome precursors. In this study, we revealed that hucMSC-ex-delivered 14-3-3 zeta interacted with ATG16L to activate autophagy. Our findings suggest that 14-3-3 zeta is a novel mechanism for MSC-exosomes-activated autophagy and provides a new strategy for the prevention of cisplatin-induced nephrotoxicity.