HIF-1-mediated macrophage metabolic reprogramming promotes AKI to CKD transition.

Macrophage is educated by the tubule epithelial cell with maladaptive repair during the renal maladaptive repair, which is one of the most important characteristic features in acute kidney injury (AKI) to chronic kidney disease (CKD) transition. However, the underlying mechanism of orchestrating characterization of macrophage in renal maladaptive repair remains largely unclear. Accordingly, we found that pro-inflammatory macrophage educated by tubule epithelial cell with maladaptive repair was the primary contributor to the renal maladaptive repair in AKI to CKD transition, because macrophages depletion significantly attenuated tubulointerstitial fibrosis. Meanwhile, we found that glycolysis was essential for maintaining pro-inflammatory macrophage phenotype. Further, we demonstrated that HIF-1α played a crucial role in macrophage glycolysis as myeloid HIF-1α knockout alleviated tubulointerstitial fibrosis and AKI to CKD transition in vivo. Mechanistically, NF-κB directly binds to the HIF-1α promoter, boosting its transcription and significantly contributing to tubulointerstitial fibrosis in the AKI to CKD transition. Blockage of NF-κB ameliorated the CKD progression following AKI in vivo. Taken together, our studies provide a novel paradigm in which pro-inflammatory macrophage orchestrates renal maladaptive repair, contributing to the AKI to CKD transition. Blockade of NF-κB-HIF-1 signaling-mediated macrophage metabolic reprogramming may provide attractive strategy for pharmacologic therapy of the AKI to CKD transition.