Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury
Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury
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DOI：
10.1172/jci85939
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发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
Fornoni, Alessia
中科院分区：
文献类型：
--
作者：
Pedigo, Christopher E.;Ducasa, Gloria Michelle;Fornoni, Alessia
高水平的循环TNF及其受体TNFR 1和TNFR 2可预测糖尿病肾病（DKD）的进展，但它们对DIM器官损伤的作用仍不清楚。在这里，我们研究了局部和全身TNF在足细胞损伤中的作用。我们将人足细胞与从DKD患者和局灶性节段性肾小球硬化症（FSGS）患者中收集的血清进行培养，DKD患者的TNF水平升高，局灶性节段性肾小球硬化症（FSGS）患者的TNF水平与健康患者相似。外源性TNF给药或局部TNF表达同样足以通过双重机制引起足细胞中游离胆固醇依赖性凋亡，所述双重机制需要减少ATP结合盒转运蛋白A1介导的（ABCA 1介导的）胆固醇流出和减少固醇-O-酰基转移酶1（SOAT 1）引起的胆固醇酯化。在足细胞特异性ABCA 1缺乏的小鼠中，TNF诱导的白蛋白尿加重，并通过环糊精清除胆固醇而部分预防。TNF刺激的足细胞游离胆固醇依赖性凋亡由活化T细胞核因子1（NFATc 1）介导。ABCA 1过表达或胆固醇耗竭足以减少足细胞特异性NFATc 1激活小鼠的白蛋白尿。我们的数据暗示了NFATc 1/ABCA 1依赖性机制，其中局部TNF足以引起游离胆固醇依赖性足细胞损伤，而不管TNF、TNFR 1或TNFR 2血清水平如何。
High levels of circulating TNF and its receptors, TNFR1 and TNFR2, predict the progression of diabetic kidney disease (DKD), but their contribution to organ damage in DIM remains largely unknown. Here, we investigated the function of local and systemic TNF in podocyte injury. We cultured human podocytes with sera collected from DKD patients, who displayed elevated TNF levels, and focal segmental glomerulosclerosis (FSGS) patients, whose TNF levels resembled those of healthy patients. Exogenous TNF administration or local TNF expression was equally sufficient to cause free cholesterol dependent apoptosis in podocytes by acting through a dual mechanism that required a reduction in ATP-binding cassette transporter A1-mediated (ABCA1-mediated) cholesterol efflux and reduced cholesterol esterification by sterol-0-acyltransferase 1 (SOAT1). TNF-induced albuminuria was aggravated in mice with podocyte-specific ABCA1 deficiency and was partially prevented by cholesterol depletion with cyclodextrin. TNF-stimulated free cholesterol-dependent apoptosis in podocytes was mediated by nuclear factor of activated T cells 1 (NFATc1). ABCA1 overexpression or cholesterol depletion was sufficient to reduce albuminuria in mice with podocyte-specific NFATc1 activation. Our data implicate an NFATc1/ABCA1-dependent mechanism in which local TNF is sufficient to cause free cholesterol-dependent podocyte injury irrespective of TNF, TNFR1, or TNFR2 serum levels.