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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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Project description:Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide with limited treatment options. The intricate pathogenesis of dysregulated lipid metabolism leading to the development of DKD remains obscure. Lipophagy, which refers to the autophagic degradation of intracellular lipid droplets, has been found to be impaired in DKD, resulting in renal tubule dysfunction and ectopic lipid deposition (ELD). The lipotoxity in renal tubules is closely related to the pathogenesis of DKD. Therefore, it is crucial to develop effective and safe agents that can restore autophagic flux and lipophagy in renal tubules for potential preventive interventions. Purpose: This study seeks to investigate the preventive effect of sodium butyrate (NaB) on ELD in the progression of DKD and elucidate the underlying mechanisms involved.Methods: The beneficial effects of NaB were investigated in glucolipotoxicity (GLT)-stimulated HK-2 cells and the streptozotocin (STZ) injection combined with a high-fat diet induced DKD model mice. Additionally, we managed to silence transcription factor EB (TFEB) in HK-2 cells and establish the renal specific silence model by retrograde ureteral infusion of AAV9-shTFEB in mice. We investigated the expression profile of RNAs in HK-2 cells through. The mechanism of NaB is demonstrated by RNA sequencing (RNA-seq), pulldown MS assay, SPR experiments etc.Results: Our findings revealed that serum butyrate level is reduced in DKD patients and is statistically correlated with urinary protein excretion and eGFR. Sodium butyrate (NaB) dose-dependently improved lipid deposition in HK-2 cells and renal tubular epithelial cells of DKD model mice. This effect may be attributed to the promotion of TFEB dephosphorylation, as NaB can directly interact with PPP2R1A to activate PP2A phosphorylation activity. Therefore, NaB may play a role in improving renal lipid deposition in DKD through the PP2A-TFEB pathway. Conclusion: NaB acts as a PP2A-TFEB axis activator that restores lipophagy to ameliorate ELD and renal dysfunction in DKD.

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

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