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Obesity and diabetes significantly elevate the risk of chronic kidney disease (CKD). While renal lipotoxicity and damage serve as markers of CKD, the mechanisms driving its progression remain poorly understood. In this study, we measured the protein levels of leucine-rich alpha-2-glycoprotein 1 (LRG1), an adipokine up-regulated in the serum of obese humans and mice, in mouse urine samples. Elevated levels of urine LRG1 were detected in obese mice fed a high-fat diet (HFD) compared to their lean counterparts. Furthermore, whole-body Lrg1 knockout mice exhibited resistance to HFD-induced lipid accumulation and tubular cell damage in the kidney, accompanied by improved ER stress and reduced Chop activity relative to wild-type littermates. Cellular studies revealed that LRG1 treatment alone induced lipid accumulation and fibrogenesis in HK-2 proximal tubule cells by inhibiting fatty acid β-oxidation (FAO) and triggering apoptosis. Moreover, co-treatment of LRG1 with low-dose palmitate acid (50 μM) had a synergistic effect on lipid accumulation in HK-2 cells. In summary, our findings suggest that LRG1 is a urinary protein, and its augmentation in urine may serve as a biomarker for obesity-induced insulin resistance and CKD. Thus, therapeutic targeting of LRG1 could represent an effective strategy to mitigate ectopic fat deposition in the kidney and prevent the exacerbation of obesity-induced CKD. Disclosure C. Wei: None. D. Morales: None. J. Ryu: None. J. Hadley: None. J. Bai: None. R. Duggirala: None. J.L. Lynch: Research Support; Beta Bionics, Inc., Novo Nordisk. L.L. Xiao: None. L.Q. Dong: None. Funding the Baptist Health Foundation
Cong et al. (Fri,) studied this question.