Liver-to-kidney apolipoprotein J trans-accumulation exacerbates diabetic renal injury by disrupting TFEB-mediated lipid homeostasis.

AIMS/HYPOTHESIS: Ectopic lipid accumulation in renal tubules induces lipotoxicity and contributes to the progression of diabetic kidney disease (DKD). Apolipoprotein J (ApoJ), a glucose-regulated, liver-derived molecular chaperone, is implicated in systemic metabolic homeostasis. This study aimed to investigate the pathophysiological role of ApoJ in the development of DKD.

METHODS

Spearman's r analysis was used to evaluate the association between circulating ApoJ concentrations and renal function in a cohort of 201 individuals with type 2 diabetes mellitus. The pathways were identified by proteomic analyses and subsequently validated using gain- and loss-of-function approaches in proximal tubular epithelial HK2 cells, tissue-specific ApoJ-knockout mice and additional mouse models of DKD.

RESULTS

In individuals with type 2 diabetes, circulating ApoJ concentrations were positively associated with indices of renal dysfunction. In murine models of DKD, elevated renal ApoJ was accompanied by increased lipid accumulation and structural kidney injury. Mechanistic studies revealed that ApoJ inhibited FBW7-mediated ubiquitination of mammalian target of rapamycin (mTOR), thereby enhancing mTOR interaction with transcription factor EB (TFEB) in HK2 cells under conditions of nutrient excess, leading to lipid imbalance and renal fibrosis. Hepatocyte-specific deletion of ApoJ eliminated circulating ApoJ, prevented its accumulation in renal tubules and ameliorated diabetic kidney injury. Furthermore, pharmacological blockade with the ApoJ antagonist MK53 reactivated the TFEB-autophagy pathway, restored lipid homeostasis and reduced renal damage in diabetic mice.

CONCLUSIONS/INTERPRETATION: Our findings highlight a liver-to-kidney interorgan transfer of pathogenetic ApoJ in diabetic kidney injury and suggest that MK53 represents a potential therapeutic strategy for DKD.