Urinary Biomarkers of AKI and Mortality 3 Years after Cardiac Surgery
Urinary Biomarkers of AKI and Mortality 3 Years after Cardiac Surgery
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DOI：
10.1681/asn.2013070742
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发表时间：
2014-05-01
影响因子：
13.6
通讯作者：
Parikh, Chirag R.
中科院分区：
文献类型：
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作者：
Coca, Steven G.;Garg, Amit X.;Parikh, Chirag R.
内皮素系统已成为治疗糖尿病肾病的新靶点。 Endothelin-1 促进系膜细胞增殖和硬化。然而，在体内尚未显示内皮素-1对足细胞的直接致病作用，并且尚未研究足细胞中的内皮素-1信号传导。本研究调查了实验性糖尿病肾病期间内皮素对足细胞的影响。用内皮素-1 刺激原代小鼠足细胞会引发由内皮素 A 型受体 (ETAR) 和内皮素 B 型受体 (ETBR) 介导的快速钙瞬变。然后，我们生成了足细胞特异性双缺失 ETAR 和 ETBR 的小鼠 (NPHS2-CrexEdnra(lox/lox)xEdnrb(lox/lox) [Pod-ETRKO]）。在体外，内皮素-1 处理增加了野生型肾小球中总 β-连环蛋白和磷酸-NF-κ B 的表达，但这种作用在 Pod-ETRKO 肾小球中减弱。注射链脲佐菌素诱导糖尿病后，野生型小鼠出现轻度糖尿病肾病，伴有微量白蛋白尿、系膜基质扩张、肾小球基底膜增厚和足细胞丢失，而 Pod-ETRKO 小鼠的蛋白尿较少，并且完全免受肾小球硬化和足细胞丢失的影响，即使在 未切除肾。此外，与对应野生型小鼠的肾小球相比，正常和糖尿病 Pod-ETRKO 小鼠的肾小球表达的总 β-连环蛋白和磷酸-NF-κ B 显着减少。这一证据表明，内皮素-1 通过直接激活足细胞中的内皮素受体以及 NF-κ B 和 β-连环蛋白途径，驱动肾小球硬化和足细胞损失的发生。值得注意的是，ETBR 亚型的表达和功能都很重要。此外，这些结果表明，足细胞中内皮素-1 通路的选择性激活介导了影响系膜结构和硬化的病理生理串扰。
The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-CrexEdnra(lox/lox)xEdnrb(lox/lox) [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total beta-catenin and phospho-NF-kappa B expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total beta-catenin and phospho-NF-kappa B compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-kappa B and beta-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis.