The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes
Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprotective. This study examined the role of PPARγ in the lipotoxic podocyte using a PPARγ knockout (PPARγKO) cell line and since the activation of PPARγ by Thiazolidinediones (TZD) is limited by their side effects, it explored other alternative therapies to prevent podocyte lipotoxic damage. Wild-type and PPARγKO podocytes were exposed to the fatty acid palmitic acid (PA) and treated with the TZD (Pioglitazone) and/or the Retinoid X receptor (RXR) agonist Bexarotene (BX). It revealed that podocyte PPARγ is essential for podocyte function. PPARγ deletion reduced key podocyte proteins including podocin and nephrin while increasing basal levels of oxidative and ER stress causing apoptosis and cell death. A combination therapy of low-dose TZD and BX activated both the PPARγ and RXR receptors reducing PA-induced podocyte damage. This study confirms the crucial role of PPARγ in podocyte biology and that their activation in combination therapy of TZD and BX may be beneficial in the treatment of obesity-related kidney disease.
Research conducted for this publication was supported by the Mobility stays abroad José Castillejo for young doctors of Ministerio de Educación Cultura y Deporte de España [CAS 12/00160], Ministerio de Economía y Competitividad de España [BFU2016-78951-R, BFU2017-90578-REDT], Ministerio de Ciencia e Innovacion [PID2020-116875RB-I00], Comunidad de Madrid (Spain) [S2017/BMD-3684, P2022/BMD-7227]. RJC was supported by the British Medical Research Council (MRC) with a Senior Clinical Fellowship [MR/K010492/1].
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