Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis
Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis
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DOI：
10.1172/jci71195
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发表时间：
2014-04-01
影响因子：
15.9
通讯作者：
Bottinger, Erwin P.
中科院分区：
文献类型：
--
作者：
Daehn, Ilse;Casalena, Gabriella;Bottinger, Erwin P.
局灶节段性肾小球硬化症（FSGS）是一种原发性肾脏疾病，通常与蛋白尿和肾小球功能进行性丧失相关，导致慢性肾脏疾病（CKD）的发展。FSGS的特征是足细胞损伤和肾小球毛细血管节段的消耗和塌陷。FSGS的进展与足细胞中的TGF-β活化相关;然而，TGF-β信号传导如何促进疾病尚不清楚。在这里，我们确定了在阿霉素诱导的肾小球硬化症的转基因小鼠和BALB/c小鼠中，足细胞特异性激活TGF-β信号与足细胞释放内皮素1（EDN 1）相关，EDN 1通过旁分泌EDN 1受体A（EDNRA）激活介导相邻内皮细胞的线粒体氧化应激和功能障碍。内皮功能障碍促进足细胞凋亡，抑制EDNRA或清除肾脏靶向ROS可预防足细胞丢失、蛋白尿、肾小球硬化和肾衰竭。我们证实了在共培养系统中足细胞和内皮细胞之间的相互串扰。FSGS患者的活检显示线粒体DNA损伤增加，与EDNRA介导的肾小球内皮线粒体氧化应激一致。我们的研究表明，节段性肾小球硬化症的发展是EDN 1/EDNRA依赖性线粒体功能障碍介导的足细胞-内皮细胞串扰的结果，并表明靶向足细胞和内皮细胞之间的相互作用可能为FSGS的治疗干预提供机会。
Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-beta activation in podocytes; however, it is not clear how TGF-beta signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-beta signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.