The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes.
The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes.
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DOI：
10.1016/j.bbalip.2023.159329
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发表时间：
2023-05
期刊：
影响因子：
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通讯作者：
Almudena G Carrasco;Adriana Izquierdo-Lahuerta;Á. Valverde;L. Ni;Elena Flores-Salguero;R. Coward;G. Medina-Gómez
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文献类型：
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作者：
Almudena G Carrasco;Adriana Izquierdo-Lahuerta;Á. Valverde;L. Ni;Elena Flores-Salguero;R. Coward;G. Medina-Gómez
足细胞是维持肾小球滤过屏障的特化上皮细胞。这些细胞在肥胖状态下易受脂肪毒性影响，在肾脏疾病导致蛋白尿和肾损伤时不可逆转地丢失。PPARγ是一种核受体，其激活可以保护肾。本研究使用PPARγ敲除（PPARγ ko）细胞系研究了PPARγ在脂毒性足细胞中的作用，由于噻唑烷二酮（TZD）对PPARγ的激活受到其副作用的限制，因此探索了其他替代疗法来预防足细胞脂毒性损伤。野生型和ppar γ - ko足细胞暴露于脂肪酸棕榈酸（PA）中，并用TZD（吡格列酮）和/或类视黄醇X受体（RXR）激动剂贝沙罗汀（BX）处理。这表明足细胞PPARγ对足细胞功能至关重要。PPARγ缺失减少了关键足细胞蛋白，包括足蛋白和肾素，同时增加了氧化和内质网应激的基础水平，导致细胞凋亡和细胞死亡。低剂量TZD和BX联合治疗可激活PPARγ和RXR受体，减轻pa诱导的足细胞损伤。本研究证实了PPARγ在足细胞生物学中的重要作用，其在TZD和BX联合治疗中的激活可能有助于治疗肥胖相关肾脏疾病。
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.