Autophagy Related 5 Promotes Mitochondrial Fission and Inflammation via HSP90‐HIF‐1 <i>α</i> ‐Mediated Glycolysis in Kidney Fibrosis

Although significant progress in identifying molecular mediators of fibrosis is made, there is still controversy regarding the role and mechanism of autophagy in kidney fibrosis. Here, this study finds that autophagy related 5 (ATG5) is obviously increased in uric acid (UA), aristolochic acid (AA) and transforming growth factor-β1 (TGF-β1)-induced HK-2 cells, as well as in kidneys from patients with chronic kidney disease (CKD) and mice with hyperuricemic nephropathy (HN), aristolochic acid nephropathy (AAN) and unilateral renal ischemia-reperfusion injury (uIRI). Conditional deletion of ATG5 in HN, AAN and uIRI murine models significantly alleviated aberrant glycolysis, attenuated pathological lesions, and improved kidney function. Mechanistically, ATG5 mediates the binding between heat shock protein 90 (HSP90) and hypoxia-inducible factor 1alpha (HIF-1α), thereby enhancing the stability of HIF-1α and further promoting the overactivation of glycolysis. Subsequently, the aberrant glycolysis facilitated the occurrence of mitochondrial fission and inflammatory response, thus leading to kidney fibrosis. Taken together, the study provides solid evidence supporting that persistent activation of ATG5 in kidney tubules promotes kidney fibrosis. The profibrotic function of ATG5 is related to the regulation on HSP90-HIF-1α-mediated glycolysis, resulting in mitochondrial fission and renal inflammation. Thus, ATG5 may be a novel therapeutic target for kidney fibrosis.