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PA up-regulates the KEGG pathway ‘Lysosome’ in cultured PTECs

ABSTRACT: Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in experimental and human obesity-related kidney disease. However, the transcriptional regulators involved in renal lipotoxicity is largely unknown. Here we found palmitic acid (PA) strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB), which was mediated by inhibition of MTORC1 (mechanistic target of rapamycin kinase complex 1) via Rag GTPase inactivation. PA-induced TFEB nuclear translocation was, however, gradually decreased over a longer treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney disease. High-fat diet (HFD)-fed proximal tubular epithelial cell (PTEC)-specific Tfeb-deficient mice exhibited greater phospholipid accumulation in enlarged lysosomes, which manifested as multilamellar bodies (MLBs). Activated TFEB mediated lysosomal exocytosis of phospholipids, to help PTECs to reduce MLBs/vacuole accumulation. Furthermore, HFD-fed PTEC-specific Tfeb-deficient mice showed autophagic stagnation and exacerbated injury upon renal ischemia-reperfusion. Finally, higher BMI was associated with increased vacuolation and decreased nuclear TFEB in the proximal tubule of CKD patients and we herein proposed a new disease concept “obesity-related tubulopathy (ORT)”. In conclusion, these results indicate a critical role of TFEB-mediated lysosomal exocytosis in counteracting renal lipotoxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE191216 | GEO | 2023/01/17

REPOSITORIES: GEO

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