HSPA12A promotes c-Myc lactylation-mediated proliferation of tubular epithelial cell to facilitate renal functional recovery from kidney ischemia/reperfusion injury

Abstract Proliferation of renal tubular epithelial cells (TEC) is essential to restore tubular integrity and thereby to support renal functional recovery from kidney ischemia/reperfusion (KI/R) injury. The transcriptional factor c-Myc is activated for TEC proliferation following KI/R; however, the in-depth mechanism of c-Myc activation in TEC following KI/R is incompletely known. Heat shock protein A12A (HSPA12A) is an atypic member of HSP70 family. In this study, we found that KI/R decreased HSPA12A expression in mouse kidneys and TEC, while ablation of HSPA12A in mice impaired TEC proliferation and renal functional recovery following KI/R. Gain-of-function studies demonstrated that HSPA12A promoted TEC proliferation upon hypoxia/reoxygenation (H/R) through directly interacting with c-Myc and enhancing its nuclear localization to increase expression of its target genes related to TEC proliferation. Notably, c-Myc was lactylated in TEC after H/R, and this lactylation was enhanced by HSPA12A overexpression. Importantly, inhibition of c-Myc lactylation attenuated the HSPA12A-induced increases of c-Myc nuclear localization, proliferation-related gene expression, and TEC proliferation. Further experiments revealed that HSPA12A promoted c-Myc lactylation via increasing lactate generation by activating the Hif1α-mediated glycolysis. The results unraveled a role of HSPA12A in promoting TEC proliferation following KI/R, and this role of HSPA12A was achieved through increasing c-Myc lactylation for its transcriptional effects. Therefore, targeting HSPA12A in TEC might be a viable strategy to promote renal functional recovery from KI/R injury in patients.