Lipotoxicity dysregulates the immunoproteasome in podocytes and kidneys in type 2 diabetes
Lipotoxicity dysregulates the immunoproteasome in podocytes and kidneys in type 2 diabetes
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DOI：
10.1152/ajprenal.00509.2020
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发表时间：
2021-04-01
影响因子：
4.2
通讯作者：
Lee, Eugene
中科院分区：
文献类型：
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作者：
Lee, Hyun Soon;Suh, Ji Yeon;Lee, Eugene
棕榈酸(PA)可导致2型糖尿病患者的脂肪毒性，并诱导足细胞氧化应激。氧化的细胞蛋白被蛋白酶体降解。蛋白酶体在PA或氧化应激诱导的足细胞损伤和糖尿病肾病(DN)发病机制中的作用尚不清楚。用免疫印迹法研究了PA对db/db和db/m小鼠培养的足细胞和肾皮质组织中205和265个蛋白酶体、蛋白酶体激活剂28(PA28)调节剂和免疫蛋白酶体表达的影响。用形态计量学方法测量db/db和db/m小鼠的肾小球面积和肾小球基底膜(GBM)宽度。PA的短期孵育或低水平的H_2O_2只能上调培养足细胞中的免疫蛋白酶体。与其他蛋白酶体一样，长期暴露于PA的足细胞最终下调免疫蛋白酶体，而油酸(OA)或二十碳五烯酸(EPA)可恢复PA诱导的蛋白水平下降。在db/db小鼠中，加入PA28α的小鼠肾皮质免疫蛋白酶体表达明显低于db/m小鼠，肾小球面积和基底膜宽度明显增加。喂食富含油酸的橄榄油或富含EPA的鱼油可保护db/db小鼠免受肾皮质免疫蛋白酶体表达减少、肾小球增大和基底膜增厚的影响。这些结果表明，脂肪毒性下调了2型糖尿病小鼠足细胞和肾脏中免疫蛋白酶体的表达，而OA和EPA对2型糖尿病小鼠肾脏皮质免疫蛋白酶体表达下降和糖尿病肾病的进展具有保护作用。鉴于此，脂毒性诱导的足细胞损伤与免疫蛋白酶体表达受损似乎在糖尿病肾病的发病机制中发挥了重要作用。值得注意的是，在足细胞中，PA迅速诱导免疫蛋白酶体表达，但最终减少，而OA和EPA则恢复了降低的免疫蛋白酶体水平。在2型糖尿病小鼠的肾皮质中，免疫蛋白酶体的表达显著减少，而饲喂富含OA的橄榄油或富含EPA的鱼油饮食可以保护它们免受免疫蛋白酶体表达减少和糖尿病肾病进展的影响。因此，脂毒性诱导的足细胞损伤与免疫蛋白酶体表达受损可能与糖尿病肾病的发病机制有关。
Palmitic acid (PA) leads to lipotoxicity in type 2 diabetes and induces oxidative stress in podocytes. Oxidized cellular proteins are degraded by proteasomes. The role of proteasomes in PA- or oxidative stress-induced podocyte injury and pathogenesis of diabetic nephropathy (DN) is unknown. We investigated the effects of PA on expression of 205 and 265 proteasomes, proteasome activator 28 (PA28) regulators, and the immunoproteasome in cultured podocytes and renal cortical tissues of db/db and db/m mice using Western blot analysis. Glomerular areas and glomerular basement membrane (GBM) widths of db/db and db/m mice were examined using morphometry. Short-term incubation of PA or low levels of H2O2 upregulated only the immunoproteasome in cultured podocytes. Long-term exposure of podocytes to PA ultimately downregulated the immunoproteasome as with other proteasomes, whereas oleic acid (OA) or eicosapentaenoic acid (EPA) restored the PA-induced decreased protein levels. In db/db mice, renal cortical immunoproteasome expression with PA28 alpha was significantly decreased compared with db/m mice, and glomerular areas and GBM widths were significantly increased compared with db/m mice. Feeding of an OA-rich olive oil or EPA-rich fish oil protected db/db mice against the reduced renal cortical immunoproteasome expression, glomerular enlargement, and GBM thickening. These results demonstrate that lipotoxicity downregulates the immunoproteasome in podocytes and kidneys in type 2 diabetes and that OA and EPA protected type 2 diabetic mice against decreased renal cortical immunoproteasome expression and the progression of DN. Given this, lipotoxicity-induced podocyte injury with impaired immunoproteasome expression appears to play an important role in the pathogenesis of DN.NEW & NOTEWORTHY In podocytes, PA rapidly induced immunoproteasome expression but ultimately decreased it, while OA and EPA restored the decreased immunoproteasome levels. In the renal cortex of type 2 diabetic mice, immunoproteasome expression was significantly decreased, whereas feeding of OA-rich olive oil or EPA-rich fish oil diets protected them against the reduced immunoproteasome expression and progression of diabetic nephropathy. Thus, lipotoxicity-induced podocyte injury with impaired immunoproteasome expression may be related to the pathogenesis of diabetic nephropathy.