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Dyslipidemia is an independent risk factor for diabetic kidney disease (DKD), but some lipid-lowering drugs are reported to exacerbate this disease, as they prohibit fatty acid oxidation (FAO) which is the primary energy source in renal proximal tubules. In this study, we demonstrated low-density lipoprotein receptor-related protein 5 (LRP5) as a novel regulator of both systemic lipid metabolism and FAO in the kidney. In Lrp5-deficient mice fed with a high-fat diet, the levels of serum lipids were significantly up-regulated, accompanied by worsened tubulointerstitial fibrosis and loss of renal tubular epithelial cells. By overexpression and knockdown of LRP5 in renal proximal epithelial cells, LRP5 was proven to be essential for maintaining the epithelial phenotype under the condition of lipotoxicity. RNA-sequencing suggested that Lrp5 deficiency greatly promoted lipid deposition but compromised the FAO in the DKD kidneys. Further analysis identified that LRP5 potentiated the activation of peroxisome proliferator-activated receptor (PPAR)/PPARgamma coactivator 1 signaling, restoring the compromised FAO in the renal proximal tubules of DKD. These results highlight a potential therapeutic role of LRP5 in promoting systemic lipid metabolism and FAO for treating DKD with dyslipidemia. Disclosure X. He: None. R. Zhang: None. S. Wen: None. X. Xiang: None. M. Cai: None. Y. Chen: None. Funding Grants from the Municipal Science and Technology Planning Projects of Guangzhou City (SL2023A03J00003), National Natural Science Foundation of China (82270886, 82000782), Sci-Tech Research Development Program of Guangzhou City (202201020589), Key Area R&D Program of Guangdong Province (2019B020227003)
HE et al. (Fri,) studied this question.