Postnatal deletion of Bmal1 in mice protects against obstructive renal fibrosis via suppressing Gli2 transcription

Abstract

Circadian clock is involved in regulating most renal physiological functions, including water and electrolyte balance and blood pressure homeostasis, however, the role of circadian clock in renal pathophysiology remains largely unknown. Here we aimed to investigate the role of Bmal1, a core clock component, in the development of renal fibrosis, the hallmark of pathological features in many renal diseases. The inducible Bmal1 knockout mice (iKO) whose gene deletion occurred in adulthood were used in the study. Analysis of the urinary water, sodium and potassium excretion showed that the iKO mice exhibit abolished diurnal variations. In the model of renal fibrosis induced by unilateral ureteral obstruction, the iKO mice displayed significantly decreased tubulointerstitial fibrosis reflected by attenuated collagen deposition and mitigated expression of fibrotic markers α-SMA and fibronectin. The hedgehog pathway transcriptional effectors Gli1 and Gli2, which have been reported to be involved in the pathogenesis of renal fibrosis, were significantly decreased in the iKO mice. Mechanistically, ChIP assay and luciferase reporter assay revealed that BMAL1 bound to the promoter of and activate the transcription of Gli2, but not Gli1, suggesting that the involvement of Bmal1 in renal fibrosis was possibly mediated via Gli2-dependent mechanisms. Furthermore, treatment with TGF-β increased Bmal1 in cultured murine proximal tubular cells. Knockdown of Bmal1 abolished, while overexpression of Bmal1 increased, Gli2 and the expression of fibrosis-related genes. Collectively, these results revealed a prominent role of the core clock gene Bmal1 in tubulointerstitial fibrosis. Moreover, we identified Gli2 as a novel target of Bmal1, which may mediate the adverse effect of Bmal1 in obstructive nephropathy.

Circadian Blood Pressure Rhythm in Cardiovascular and Renal Health and Disease

“…On the other hand, upon adenine treatment, Clock mutant mice showed significantly higher BP and worse renal function than control mice, implying the circadian BP disruption enhances the susceptibility to chronic kidney disease [91]. However, our own recent study found that postnatal Bmal1 deletion in mice protected against renal fibrosis via suppressing Gli2 transcription, which provides a prominent role of the core clock gene Bmal1 in tubulointerstitial fibrosis [92]. Nevertheless, more efforts need to be made from different point of view to further clarify the relationship between circadian BP disruption and chronic kidney diseases.…”

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

“…BMAL1 is the main transcriptional activator of the circadian clock, which has been shown to regulate the progress of various renal diseases. 7 , 8 , 9 , 10 However, researches on its function in renal IRI are limited. Previous studies have revealed that the expression level of BMAL1 in cardiac and cerebral tissues decreased significantly after IR, 17 , 28 , 29 which is in line with our study showing that renal IR causes a dramatic decrease in BMAL1 expression level in renal tissues.…”

“…BMAL1 is the main transcriptional activator of the circadian clock, which has been shown to regulate the progress of various renal diseases 7–10 . However, researches on its function in renal IRI are limited.…”

“… 9 In the model of renal fibrosis caused by unilateral ureteral obstruction, inducible BMAL1‐knockout mice whose gene deletion occurred in adulthood showed less renal tubular fibrosis. 10 However, there is no evidence to clarify the role of BMAL1 in renal IRI.…”

“…In whole nephron‐specific BMAL1‐knockout mice, the deletion of BMAL1 can lead to renal mitochondrial dysfunction and abnormal pharmacokinetics 9 . In the model of renal fibrosis caused by unilateral ureteral obstruction, inducible BMAL1‐knockout mice whose gene deletion occurred in adulthood showed less renal tubular fibrosis 10 . However, there is no evidence to clarify the role of BMAL1 in renal IRI.…”