Kidney international · 2026
Tubular Rev-erbα deficiency aggravates kidney fibrosis via transcription factor NFIL3-driven lipid accumulation.
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Wang Xiao-Lan, Cheng Jia, Zhu Yuting, Xiang Huiling, Yuan Qian, Meng Xianfang, Zhang Chun
Аннотация
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.
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.