Human immunodeficiency virus downregulates podocyte apoE expression
Human immunodeficiency virus downregulates podocyte apoE expression
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DOI：
10.1152/ajprenal.90668.2008
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发表时间：
2009-09-01
影响因子：
4.2
通讯作者：
Singhal, Pravin C.
中科院分区：
文献类型：
--
作者：
Arora, Shitij;Husain, Mohammad;Singhal, Pravin C.
Arora S，Husain M，Kumar D，Patni H，Pathak S，Mehrotra D，Reddy VK，Reddy LR，Salhan D，Yadav A，Mathieson PW，Saleem MA，Chander PN，Singhal PC.人类免疫缺陷病毒下调足细胞apoE表达。美国肾脏生理学杂志297：F653-F661，2009年。首次发表于2009年6月24日; doi：10.1152/ajprenal.90668.2008。载脂蛋白E（apoE）已被证明在保护肾小球系膜细胞免受损伤中发挥重要作用。在本研究中，我们评估了载脂蛋白E及其相关下游效应在人类免疫缺陷病毒（HIV）相关肾病（HIVAN）中的作用。对照组（n = 6）和年龄和性别匹配的HIV-1转基因小鼠（Tg 26，n = 6）评价其肾皮质apoE表达。Tg 26小鼠的肾组织不仅显示apoE表达降低，而且还显示串珠素mRNA表达下调。在体外研究中，用NL 4 - 3 HIV（缺乏gag和pol的HIV-1构建体，用于开发Tg 26小鼠模型; NL 4 -3/CIHP）或空载体（EV/CIHP）转导条件永生化的人足细胞（CIHP）;研究NL 4 -3/CIHP和EV/CIHP的apoE mRNA表达。与EV/CIHP相比，NL 4 -3/CIHP显示apoE表达降低。为了评估HIV-1基因在apoE表达调节中的作用，用单个HIV-1基因构建体转导条件永生化小鼠足细胞（CIMPs）。只有nef转导的CIMPs显示apoE表达减少。为了证实nef在CIHP中的这种作用，在nef/CIHP和EV/CIHP的稳定集落中进行微阵列分析。nef/CIHP显示apoE降低60%，硫酸乙酰肝素mRNA表达降低90%。此外，nef转基因小鼠的肾组织表达的apoE和串珠素的减少。Tg 26和nef转基因小鼠也显示出肾小球系膜细胞增殖的区域。这些结果表明，HIV-1诱导的足细胞apoE表达的减少和足细胞串珠素的相关下调可能有助于HIVAN的系膜细胞（MC）表型。
Arora S, Husain M, Kumar D, Patni H, Pathak S, Mehrotra D, Reddy VK, Reddy LR, Salhan D, Yadav A, Mathieson PW, Saleem MA, Chander PN, Singhal PC. Human immunodeficiency virus downregulates podocyte apoE expression. Am J Physiol Renal Physiol 297: F653-F661, 2009. First published June 24, 2009; doi:10.1152/ajprenal.90668.2008.-Apolipoprotein E (apoE) has been demonstrated to play an important role in providing protection against mesangial cell injury. In the present study, we evaluated the role of apoE and its associated downstream effects in human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). Control (n = 6) and age-and sex-matched HIV-1 transgenic mice (Tg26, n = 6) were evaluated for their renal cortical expression of apoE. Renal tissue from Tg26 mice not only showed decreased apoE expression but also displayed downregulation of perlecan mRNA expression. In in vitro studies, conditionally immortalized human podocytes (CIHPs) were transduced with either NL4-3HIV (an HIV-1 construct lacking gag and pol, used for the development of Tg26 mouse model; NL4-3/CIHP) or empty vector (EV/CIHP); NL4-3/CIHPs and EV/CIHPs were studied for apoE mRNA expression. NL4-3/CIHPs showed reduction in apoE expression compared with EV/CIHPs. To evaluate the role of HIV-1 genes in the modulation of apoE expression, conditionally immortalized mouse podocytes (CIMPs) were transduced with individual HIV-1 gene constructs. Only nef-transduced CIMPs showed a decrease in apoE expression. To confirm this effect of nef in CIHPs, microarray analysis was performed in stable colonies of nef/CIHPs and EV/CIHPs. nef/CIHPs showed a 60% decrease in apoE and a 90% reduction in heparan sulfate mRNA expression. Moreover, nef transgenic mice showed a decrease in renal tissue expression of both apoE and perlecan. Both Tg26 and nef transgenic mice also showed areas of mesangial cell proliferation. These findings suggest that HIV-1-induced reduction in podocyte apoE expression and associated downregulation of podocyte perlecan might be contributing to mesangial cell (MC) phenotype in HIVAN.