Nr1d1 Deficiency in Renal Proximal Tubular Cells Aggravates Kidney Fibrosis by Increasing Lipid Accumulation

Background: Renal functions are closely associated with circadian rhythms. However, the specific role and mechanism of clock genes in kidney pathophysiology remain unclear. Here, we aim to investigate the function of core clock molecular-nuclear receptor subfamily 1, group D member 1 (Nr1d1) in the development of chronic kidney diseases (CKD) and how it works. Methods: CKD mouse model was established by unilateral ureteral obstruction. Renal proximal tubular cell-specific Nr1d1 knockout mice were generated. The effect of Nr1d1 was further evaluated by injection of the agonist SR9009 in CKD mice. The downstream of Nr1d1 was examined through chromatin immunoprecipitation. Results: 1. Down-regulation of Nr1d1 exacerbated renal fibrosis in UUO-induced CKD mice. 2. Nr1d1 deficiency increased lipid accumulation in renal proximal tubular cells through targeting nuclear factor interleukin 3-regulated (NFIL3). 3. The Nr1d1 agonist SR9009 alleviated renal fibrosis and lipid deposition in CKD mice. Conclusion: Our findings suggest that Nr1d1 deficiency aggravates renal fibrosis via targeting Nfil3 to increase lipid accumulation in renal proximal tubular cells in CKD mice. Funding: Government Support – Non-U.S.