Vascular smooth muscle cells contribute to APOL1-induced podocyte injury in HIV milieu.
Vascular smooth muscle cells contribute to APOL1-induced podocyte injury in HIV milieu.
复制标题
DOI：
10.1016/j.yexmp.2015.03.020
复制
发表时间：
2015-06
影响因子：
3.6
通讯作者：
Singhal, Pravin C.
中科院分区：
文献类型：
--
作者：
Lan, Xiqian;Wen, Hongxiu;Saleem, Moin A.;Mikulak, Joanna;Malhotra, Ashwani;Skorecki, Karl;Singhal, Pravin C.
临床报告表明，非裔美国人中非糖尿病性肾小球硬化的发生率较高可归因于APOL 1基因中的两个编码序列变体（G1和G2）;然而，其潜在机制仍不清楚。肾活检数据表明APOL 1/APOL 1变体（Vs）在肾血管平滑肌细胞（SMC）中的表达增强。由于APOL 1是一种相对低分子量（41 kDa）的分泌蛋白，因此SMC可能是渗透足细胞的肾小球毛细血管灌流液中APOL 1野生型（WT）/APOL 1Vs的内分泌/旁分泌来源。在本研究中，我们检验了HIV环境刺激动脉SMC分泌APOL 1及其风险变体导致足细胞损伤的假设。用HIV感染的外周血单个核细胞的条件培养基（CM）（PBMC/HIV-CM）、HIV感染的U939细胞的CM或重组IFN-γ处理的人脐动脉平滑肌细胞（HSMCs）显示APOL 1表达增强。在trans-well中与过表达APOL 1 WT的HSMC共培养的足细胞显示出损伤诱导;然而，与过表达APOL 1G 1或APOL 1G 2的HSMC共培养的足细胞显示出数倍于过表达APOL 1 WT的HSMC的损伤。与HSMC/APOL 1 WT-CM相比，从HSMC过表达APOL 1G 1/APOL 1G 2（HSMC/APOL 1G 1-CM或HSMC/APOL 1G 2-CM）收集的条件培养基也显示出更高百分比的以肿胀细胞、溶酶体渗漏、活力丧失形式的受损足细胞，以及对不利宿主因子的敏感性增强。值得注意的是，与HSMC/APOL 1G 1/G2-CM相比，HSMC/APOL 1 WT-CM仅在显著更高的浓度下促进足细胞损伤。我们的结论是，HSMCs可以作为内分泌/旁分泌来源的APOL 1Vs，介导加速足细胞损伤的HIV环境。
Clinical reports have demonstrated that higher rates of non-diabetic glomerulosclerosis in African Americans can be attributed to two coding sequence variants (G1 and G2) in the APOL1 gene; however, the underlying mechanism is still unknown. Kidney biopsy data suggest enhanced expression of APOL1/APOL1 variants (Vs) in smooth muscle cells (SMCs) of renal vasculature. Since APOL1 is a secretory protein of relatively low molecular weight (41 kDa), SMCs may be a contributory endocrine/paracrine source of APOL1 wild type (WT)/APOL1Vs in the glomerular capillary perfusate percolating podocytes. In the present study, we tested the hypothesis that an HIV milieu stimulated secretion of APOL1 and its risk variants by arterial SMCs contributes to podocyte injury. Human umbilical artery smooth muscle cells (HSMCs)-treated with conditioned media (CM) of HIV-infected peripheral mononuclear cells (PBMC/HIV-CM), CM of HIV-infected U939 cells, or recombinant IFN-γ displayed enhanced expression of APOL1. Podocytes co-cultured in trans-wells with HSMCs-over expressing APOL1WT showed induction of injury; however, podocytes co-cultured with HSMC-over expressing either APOL1G1 or APOL1G2 showed several fold greater injury when compared to HSMC- over expressing APOL1WT. Conditioned media collected from HSMC-over-expressing APOL1G1/APOL1G2 (HSMC/APOL1G1-CM or HSMC/APOL1G2-CM) also displayed higher percentages of injured podocytes in the form of swollen cells, leaky lysosomes, loss of viability, and enhanced sensitivity to adverse host factors when compared to HSMC/APOL1WT-CM. Notably, HSMC/APOL1WT-CM promoted podocyte injury only at a significantly higher concentrations compared to HSMC/APOL1G1/G2-CM. We conclude that HSMCs could serve as an endocrine/paracrine source of APOL1Vs, which mediate accelerated podocyte injury in HIV milieu.
登录
查看更多内容
DOI：
10.1126/science.1193032
发表时间：
2010-08-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Genovese G;Friedman DJ;Ross MD;Lecordier L;Uzureau P;Freedman BI;Bowden DW;Langefeld CD;Oleksyk TK;Uscinski Knob AL;Bernhardy AJ;Hicks PJ;Nelson GW;Vanhollebeke B;Winkler CA;Kopp JB;Pays E;Pollak MR
通讯作者：
Pollak MR
影响因子：
13.6
作者：
Bruggeman, Leslie A.;O'Toole, John F.;Kalayjian, Robert C.
通讯作者：
Kalayjian, Robert C.
影响因子：
19.6
作者：
通讯作者：
--
影响因子：
3.2
作者：
Kopp JB
通讯作者：
Kopp JB
影响因子：
13.6
作者：
Kopp, Jeffrey B.;Nelson, George W.;Winkler, Cheryl A.
通讯作者：
Winkler, Cheryl A.