BMAL1 regulates mitochondrial homeostasis in renal ischaemia‐reperfusion injury by mediating the SIRT1/PGC‐1α axis

The regulation of renal function by circadian gene BMAL1 has been recently recognized; however, the role and mechanism of BMAL1 in renal ischaemia-reperfusion injury (IRI) are still unknown. The purpose of this study was to clarify the pathophysiological role of BMAL1 in renal IRI. We measured the levels of BMAL1 and mitochondrial biogenesis-related proteins, including SIRT1, PGC-1α, NRF1 and TFAM, in rats with renal IRI. In rats, the level of BMAL1 decreased significantly, resulting in inhibition of SIRT1 expression and mitochondrial biogenesis. In addition, under hypoxia and reoxygenation (H/R) stimulation, BMAL1 knockdown decreased the level of SIRT1 and exacerbated the degree of mitochondrial damage and apoptosis. Overexpression of BMAL1 alleviated H/R-induced injury. Furthermore, application of the SIRT1 inhibitor EX527 not only reduced the activities of SIRT1 and PGC-1α but also further aggravated mitochondrial dysfunction and partially reversed the protective effect of BMAL1 overexpression. Moreover, whether in vivo or in vitro, the application of SIRT1 agonist resveratrol rescued the mitochondrial dysfunction caused by H/R or IRI by activating mitochondrial biogenesis. These results indicate that BMAL1 is a key circadian gene that mediates mitochondrial homeostasis in renal IRI through the SIRT1/PGC-1α axis, which provides a new direction for targeted therapy for renal IRI.