Tubular Rev-erbα deficiency aggravates kidney fibrosis via transcription factor NFIL3-driven lipid accumulation.

INTRODUCTION

Kidney metabolism and physiology exhibit circadian oscillations, which are governed by the internal circadian clock. Intracellular lipid accumulation is known to play a critical role in the pathogenesis of kidney fibrosis. However, whether and how circadian disruption accelerates the progression of kidney fibrosis remains poorly understood.

METHODS

To investigate the effects of circadian disruption on the kidney, a mouse model simulating shift work conditions was utilized. To further elucidate the role of circadian disruption in the pathogenesis and progression of kidney fibrosis, we generated a conditional knockout mouse model (KSPNr1d1KO) with specific deletion of molecular clock Rev-erbα in kidney tubular epithelial cells. Using both KSPNr1d1 KO and control mice, we subsequently established two distinct models of kidney fibrosis.

RESULTS

In this study, we observed that circadian disruption perturbs fatty acid metabolism in the renal cortex. Rev-erbα was downregulated in two mouse models of kidney fibrosis: unilateral ureteral obstruction (UUO) and folic acid nephropathy. Tubular Rev-erbα deficiency exacerbated kidney fibrosis in both UUOand unilateral kidney ischemia-reperfusion injury- induced fibrosis models, whereas administration of the Rev-erbα agonist SR9009 attenuated fibrosis in mice. Further mechanistic studies revealed that Rev-erbα deficiency disrupted fatty acid metabolism in the kidney cortex, leading to enhanced lipid accumulation through direct transcriptional repression of Nfil3.

CONCLUSIONS

Our findings demonstrate that Rev-erbα protects against kidney fibrosis by suppressing NFIL3-mediated lipid accumulation. These results suggest a vicious cycle between circadian disruption and kidney fibrosis identifying tubular Rev-erbα as a potential therapeutic target for fibrosis-related kidney diseases.