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

Apr 4, 2021FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Removing Bmal1 after birth in mice may protect kidneys from scarring by reducing Gli2 activity

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Inducible Bmal1 knockout mice exhibit abolished diurnal variations in urinary water, sodium, and potassium excretion.

Bmal1 knockout significantly reduced tubulointerstitial fibrosis in a renal fibrosis model.
Decreased collagen deposition and lower expression of fibrotic markers α-SMA and fibronectin were observed in knockout mice.
The transcription factors Gli1 and Gli2, associated with renal fibrosis, were significantly reduced in the Bmal1 knockout mice.
Bmal1 was found to bind and activate the transcription of Gli2, suggesting a potential mechanism for its role in renal fibrosis.
Treatment with TGF-β increased Bmal1 levels in cultured murine proximal tubular cells, indicating a possible regulatory relationship.

AI simplified

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.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text (XML) ↗View full text ↗

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

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief