Obesity-related proximal tubulopathy: an emerging threat to kidney health

Our previous studies have demonstrated that lipid overload leads to lysosomal dysfunction and autophagic stagnation in kidney proximal tubular epithelial cells (PTECs), which contributes to the renal lipotoxicity and eventually leading to the development of an obesity-related kidney disease. Here we identified that TFEB (transcription factor EB) is a modulator of PTECs lipotoxicity. Exposure to saturated fatty acid enhanced TFEB dephosphorylation and nuclear translocation in PTECs. In a mouse model fed with a high-fat diet (HFD), activated TFEB counteracted phospholipid accumulation in lysosomes by promoting lysosomal exocytosis in PTECs. Conversely, HFD-fed, PTECs-specific tfeb ^-/- deficient mice exhibited increased phospholipid accumulation and autophagic stagnation, which made kidney vulnerable to injury following ischemia-reperfusion. Moreover, a higher body mass index was correlated to reductions in TFEB nuclear translocation in PTECs of chronic kidney disease patients. These data suggest that PTECs are involved in the pathogenesis of obesity-related kidney disease, which is called obesity-related proximal tubulopathy. Abbreviations: EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GAP: GTPase activating protein; HFD: high-fat diet; I/R: ischemia-reperfusion; LMP: lysosomal membrane permeabilization; LRP2: low density lipoprotein receptor-related protein 2; MLBs: multilamellar bodies; MTORC1: mechanistic target of rapamycin kinase complex 1; ORT: obesity-related proximal tubulopathy; PA: palmitic acid; PTEC: proximal tubular epithelial cell; RRAG: Ras related GTP binding; RPS6KB1, ribosomal protein S6 kinase B1; TFEB: transcription factor EB.