HIV-1 Tat reduces nephrin in human podocytes: a potential mechanism for enhanced glomerular permeability in HIV-associated nephropathy
HIV-1 Tat reduces nephrin in human podocytes: a potential mechanism for enhanced glomerular permeability in HIV-associated nephropathy
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DOI：
10.1097/qad.0b013e328012c522
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发表时间：
2007-02-01
期刊：
影响因子：
3.8
通讯作者：
Camussi, Giovanni
中科院分区：
文献类型：
--
作者：
Doublier, Sophie;Zennaro, Cristina;Camussi, Giovanni
目的：探讨HIV-1 Tat是否可直接改变hiv相关性肾病（HIVAN）患者肾小球通透性。设计：重度蛋白尿是hiv的标志。狭缝隔膜是最终的肾小球滤过屏障，对维持肾脏超滤单元的效率至关重要。在本研究中，我们评估了Tat蛋白对离体肾小球通透性的直接影响，以及对人培养足细胞中肾素（主要隔膜成分）表达的影响。方法：通过测定离体大鼠肾小球对白蛋白的通透性来研究其通透性。免疫荧光法和Western blot法检测人培养足细胞中nephrin的表达。结果：我们发现Tat增加了离体肾小球的白蛋白通透性，并迅速诱导培养足细胞中肾素的重新分布和损失。用阻断抗体预处理肾小球和足细胞表明，Tat通过参与血管内皮生长因子受体2型和3型以及整合素α vB3来降低nephrin的表达。用两种血小板活化因子（PAF）受体拮抗剂对足细胞进行预孵育，可防止Tat诱导的肾素丢失和再分配，这表明PAF是Tat作用的细胞内介质。诱导足细胞快速合成PAF。当转染过表达PAF的主要分解代谢酶PAF-乙酰水解酶的足细胞受到Tat刺激时，肾素的重新分布和损失被消除。结论：本研究结果明确了Tat可能降低足细胞中nephrin的表达，从而增加肾小球通透性的机制。这为理解hiv的发病机制提供了新的见解。(c) 2007年Lippincott Williams & Wilkins。
Objective: To determine whether HIV-1 Tat may directly alter glomerular permeability in HIV-associated nephropathy (HIVAN).Design: Heavy proteinuria is a hallmark of HIVAN. The slit diaphragm is the ultimate glomerular filtration barrier critical for maintaining the efficiency of the ultrafiltration unit of the kidney. In this study, we evaluated the direct effect of Tat protein on the permeability of isolated glomeruli and on the expression of nephrin, the main slit diaphragm component, by human cultured podocytes.Methods: Permeability was studied by measuring the permeability to albumin in isolated rat glomeruli. We also evaluated the expression of nephrin in human cultured podocytes by using immunofluorescence and Western blot.Results: We found that Tat increased albumin permeability in isolated glomeruli, and rapidly induced the redistribution and loss of nephrin in cultured podocytes. Pretreatment of glomeruli and podocytes with blocking antibodies showed that Tat reduced nephrin expression by engaging vascular endothelial growth factor receptors types 2 and 3 and the integrin alpha vB3. Pre-incubation of podocytes with two platelet-activating factor (PAF) receptor antagonists prevented the loss and redistribution of nephrin induced by Tat, suggesting that PAF is an intracellular mediator of Tat action. Tat induced a rapid PAF synthesis by podocytes. When podocytes transfected to over-express PAF-acetylhydrolase, the main catabolic enzyme of PAF, were stimulated with Tat, the redistribution and loss of nephrin was abrogated.Conclusion: The present results define a mechanism by which Tat may reduce nephrin expression in podocytes, thus increasing glomerular permeability. This provides new insights in the understanding of HIVAN pathogenesis. (c) 2007 Lippincott Williams & Wilkins.