Circadian gene BMAL1 ameliorates renal ischaemia-reperfusion injury in diabetic mice by enhancing mitophagy via the HIF-1/BNIP3 pathway

Abstract

Abstract Diabetic kidneys are particularly vulnerable to ischemia/reperfusion injury (I/RI). Although previous research has suggested that the circadian gene brain and muscle ARNT-like 1 (BMAL1) plays a role in regulating renal function, the exact functions and mechanisms of BMAL1 in diabetic renal I/RI remain elusive. In this study, bilateral renal artery ligation and release were performed in non-diabetic (db/+) and diabetic (db/db) mice. In diabetic kidneys, experimental findings demonstrated a significant decrease in BMAL1 expression, along with the inhibition of the HIF-1α/BNIP3 signaling pathway and compromised mitophagy. BMAL1 overexpression alleviated cell damage and apoptosis under high glucose and hypoxia/reoxygenation stimulation. Inhibition of the Hypoxia-inducible factor-1α (HIF-1α)/ B-cell lymphoma-2 interacting protein 3 (BNIP3) pathway by the HIF-1α inhibitor PX-478 intensified cellular damage and reduced the protective effect of BMAL1 overexpression in TCMK-1 cells. These results indicate that BMAL1 regulates mitophagy in diabetic renal I/RI through the HIF-1α/BNIP3 pathway, providing valuable insights for the development of targeted therapies for diabetic renal I/RI.