Targeting accumulated apolipoprotein J in renal tubules halts the mTOR-TFEB interaction and relieves diabetic kidney disease

Ectopic lipid accumulation in renal tubules leads to lipotoxicity and exacerbates the progression of diabetic kidney disease (DKD). Apolipoprotein J (ApoJ) functions as a stress-induced molecular chaperone and participates in lipid homeostasis. As a hepatocyte-secreted entity, the involvement of ApoJ in the pathogenesis of extrahepatic organs remains poorly understood. Herein, serum ApoJ levels have been found to correlate with glycemic profiles, renal function parameters, and disease progression in individuals with Type-II diabetes. Accumulation of ApoJ in renal tubules was observed in mouse models of DKD and confirmed pathologically by renal overexpression of ApoJ in db/db mice. Under nutrient overload, ApoJ disrupts lipid and redox homeostasis and promotes epithelial-mesenchymal transition of proximal tubular cells by facilitating mTOR and transcription factor EB (TFEB) interaction. Consequently, targeting ApoJ promotes TFEB activation, restores autophagy, and alleviates renal injuries. By using tissue-specific knockout mice, we further demonstrated that the liver serves as a major source contributing to the ApoJ accumulated in renal tubules. Finally, the application of an MK53 peptide antagonizes ApoJ chaperone activity, thereby relieving disease progression of DKD. In summary, these findings suggest that ApoJ promotes diabetic renal pathogenesis through mTOR-TFEB-autophagy axis, and MK53 peptide emerges as a novel therapeutic strategy against DKD.