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 <i>vmp1-</i>knockout mice (<i>vmp1-</i>cKO) display more severe renal injuries when challenged with cisplatin or IRI. In line with this, aging <i>vmp1-</i>cKO mice spontaneously develop defective calcium metabolism and display significant tubular damage. In contrast, adenovirus-mediated <i>Vmp1</i> 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. <i>VMP1</i> 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.

巨自噬（Macroautophagy，又称自噬）激活可保护肾近端小管上皮细胞（renal proximal tubular epithelial cells，PTECs）免受多种诱因诱发的急性肾损伤（acute kidney injury，AKI）。不过，调控PTECs自噬的具体机制仍未完全阐明。本研究发现，空泡膜蛋白1（vacuole membrane protein 1，VMP1）在维持PTECs在AKI条件下的高自噬流过程中发挥关键作用。AKI患者的PTECs中VMP1表达显著上调，而慢性肾病（chronic kidney disease，CKD）患者则无此变化。在顺铂（cisplatin）或缺血再灌注损伤（ischemia-reperfusion injury，IRI）诱导的小鼠AKI模型中，均验证了AKI发生时PTECs中VMP1表达会快速升高。肾近端小管上皮细胞特异性vmp1敲除小鼠（vmp1-cKO）经顺铂或IRI攻击后，肾损伤程度更为严重。与此一致的是，衰老的vmp1-cKO小鼠会自发出现钙代谢紊乱，并表现出显著的肾小管损伤。与之相反，通过腺病毒介导的肾小管Vmp1过表达，可缓解IRI或顺铂诱导的肾小管损伤。机制层面，VMP1的表达水平与分布模式与自噬标志物微管相关蛋白1轻链3（MAP1LC3/LC3）和SQSTM1相关，且VMP1可促进肾小管细胞自噬体的形成。VMP1缺失还会导致肾小管细胞内脂滴（lipid droplets）蓄积。综上，本研究揭示了VMP1通过促进肾小管细胞自噬流与脂质代谢，在抵御AKI过程中发挥关键保护作用。