GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway.
GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway.
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DOI：
10.7150/ijbs.64665
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发表时间：
2022
影响因子：
9.2
通讯作者：
Ma KL
中科院分区：
文献类型：
--
作者：
Lu J;Chen PP;Zhang JX;Li XQ;Wang GH;Yuan BY;Huang SJ;Liu XQ;Jiang TT;Wang MY;Liu WT;Ruan XZ;Liu BC;Ma KL
背景：G蛋白偶联受体43(GPR43)是一种参与胆固醇代谢的转录后调节因子。本研究旨在探讨GPR43激活在糖尿病肾病足细胞脂肪毒性中的可能作用及其可能机制。方法：采用糖尿病GPR43基因敲除小鼠和足细胞培养模型进行实验。分别用BODIPY染色和胆固醇定量检测肾组织中脂质沉积和游离胆固醇水平。用实时定量聚合酶链式反应、免疫荧光染色和Western blotting检测肾组织和足细胞中GPR43、LC3II、p62、BEKIN1、低密度脂蛋白受体(LDLR)和早期生长反应蛋白1(Egr1)的蛋白表达。结果：糖尿病小鼠血浆低密度脂蛋白水平升高，肾脏胆固醇蓄积。然而，GPR43基因敲除抑制了这些变化。体外研究进一步证明，醋酸盐处理可诱导高糖刺激的足细胞胆固醇积聚，这与低密度脂蛋白受体介导的胆固醇摄取增加和胆固醇自噬降解减少有关，其特征是抑制了LC3成熟、p62降解和自噬小体的形成。GPR43的基因敲除或药物抑制可阻止这些对足细胞的影响。此外，GPR43的激活增加了足细胞中细胞外调节蛋白激酶1/2(ERK1/2)的活性和Egr1的表达，从而增加了胆固醇内流和自噬抑制。相反，GPR43缺失后，足细胞的这些变化得到了改善，体内和体外的结果表明。结论：GPR43激活介导的脂毒性通过调节ERK/Egr1通路参与糖尿病肾病足细胞损伤。
Background: G-protein-coupled receptor 43 (GPR43) is a posttranscriptional regulator involved in cholesterol metabolism. This study aimed to investigate the possible roles of GPR43 activation in podocyte lipotoxicity in diabetic nephropathy (DN) and explore the potential mechanisms. Methods: The experiments were conducted by using diabetic GPR43-knockout mice and a podocyte cell culture model. Lipid deposition and free cholesterol levels in kidney tissues were measured by BODIPY staining and quantitative cholesterol assays, respectively. The protein expression of GPR43, LC3II, p62, beclin1, low-density lipoprotein receptor (LDLR) and early growth response protein 1 (EGR1) in kidney tissues and podocytes was measured by real-time PCR, immunofluorescent staining and Western blotting. Results: There were increased LDL cholesterol levels in plasma and cholesterol accumulation in the kidneys of diabetic mice. However, GPR43 gene knockout inhibited these changes. An in vitro study further demonstrated that acetate treatment induced cholesterol accumulation in high glucose-stimulated podocytes, which was correlated with increased cholesterol uptake mediated by LDLR and reduced cholesterol autophagic degradation, as characterized by the inhibition of LC3 maturation, p62 degradation and autophagosome formation. Gene knockdown or pharmacological inhibition of GPR43 prevented these effects on podocytes. Furthermore, GPR43 activation increased extracellular regulated protein kinases 1/2 (ERK1/2) activity and EGR1 expression in podocytes, which resulted in an increase in cholesterol influx and autophagy inhibition. In contrast, after GPR43 deletion, these changes in podocytes were improved, as shown by the in vivo and in vitro results. Conclusion: GPR43 activation-mediated lipotoxicity contributes to podocyte injury in DN by modulating the ERK/EGR1 pathway.
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影响因子：
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FinnDiane Study Group
DOI：
10.1152/ajpendo.00229.2010
发表时间：
2011-01-01
影响因子：
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作者：
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影响因子：
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