Renal tubular VMP1 protects against acute kidney injury via modulating autophagy and autophagy-independent pathway

Macroautophagy/Autophagy activation protects renal proximal tubular epithelial cells (PTECs) against acute kidney injury (AKI) induced by various challenges. The mechanism that regulates Autophagy in PTECs, however, remains incompletely understood. Here, we report that VMP1 (vacuole membrane protein 1) plays an essential role in enabling PTECs to maintain high autophagic flow under AKI conditions. VMP1 in PTECs is strongly upregulated in AKI patients but not chronic kidney disease patients. The rapid elevation of VMP1 expression in PTECs during AKI is validated in mouse AKI models induced by cisplatin or ischemia-reperfusion injury (IRI). PTECs-specific vmp1-knockout mice (vmp1-cKO) display more severe renal injuries when challenged with cisplatin or IRI. In line with this, aging vmp1-cKO mice spontaneously develop defective calcium metabolism and display significant tubular damage. In contrast, adenovirus-mediated Vmp1 expression in renal tubular rescues IRI or cisplatin-induced renal tubular injury. Mechanistically, the level and distribution pattern of VMP1 are associated with the Autophagy markers MAP1LC3/LC3 and SQSTM1, and VMP1 facilitates the formation of renal tubular cell autophagosomes. VMP1 deficiency also results in the accumulation of lipid droplets in renal tubular cells. Our studies thus reveal a critical role of VMP1 in protecting against AKI via facilitating tubular cell autophagic flux and lipid metabolism.

Acute kidney injury; cisplatin; ischemia-reperfusion injury; lipid droplet; proximal tubular cells; vacuole membrane protein 1.