Human immunodeficiency virus-1 induces loss of contact inhibition in podocytes
Human immunodeficiency virus-1 induces loss of contact inhibition in podocytes
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DOI：
10.1681/asn.v1281677
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发表时间：
2001-08-01
影响因子：
13.6
通讯作者：
Klotman, PE
中科院分区：
文献类型：
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作者：
Schwartz, EJ;Cara, A;Klotman, PE
人类免疫缺陷病毒相关肾病（HIVAN）影响高达10%的艾滋病毒阳性黑人成人和儿童，是感染者肾脏疾病的主要原因。该病的特点是肾上皮细胞增生，包括肾小球和肾小管。病变肾脏增大，肾小球内脏上皮细胞（足细胞）表达增殖标志物。在表达HIV-1缺失结构的转基因小鼠HIVAN模型中，观察到相同的病理特征。结果表明，HIV-1 mRNA在转基因小鼠和HIVAN患者的肾上皮中表达，提示HIV-1在人和小鼠模型的疾病发病机制中都有直接作用。为了研究足细胞增殖变化的机制，将HIV-1转基因小鼠培育到永生化小鼠背景下，建立了条件永生化的转基因和非转基因足细胞细胞系。与非转基因足细胞相比，转基因足细胞在融合时表现出更高的自发增殖能力，并且发现它们在细胞周期的增殖期具有更高的细胞百分比。令人惊讶的是，转基因足细胞在软琼脂中不受接触抑制而形成聚集体。当非转基因足细胞被用于产生转基因模型的相同HIV-1构建体感染时，也会形成聚集体。这表明，接触抑制的丧失是由于HIV-1的直接影响。因此，由HIV-1基因表达诱导的增殖可能在HIVAN的发病机制中起关键作用。
Human immunodeficiency virus-associated nephropathy (HIVAN) affects up to 10% of HIV-positive black adults and children and is the leading cause of renal disease in infected individuals. The disease is characterized by proliferation of renal epithelial cells, both glomerular and tubular. Diseased kidneys are enlarged, and glomerular visceral epithelial cells (podocytes) express proliferation markers. In a transgenic murine model of HIVAN expressing a deletion construct of HIV-1, the identical pathologic features are observed. It was demonstrated that HIV-1 mRNA is expressed in renal epithelium of the transgenic mouse and in patients with HIVAN, suggesting a direct role for HIV-1 in disease pathogenesis in both humans and the murine model. For investigating the mechanisms responsible for proliferative changes in podocytes, the HIV-1 transgenic mouse was bred onto the immortomouse background, and conditionally immortalized transgenic and nontransgenic podocyte cell lines were established. Transgenic podocytes demonstrated increased spontaneous proliferation, compared with nontransgenic podocytes at confluence, and they were found to have a greater percentage of cells in the proliferative phase of the cell cycle. It is striking that transgenic podocytes were not contact inhibited and formed aggregates in soft agar. Aggregates also formed when nontransgenic podocytes were infected with the identical HIV-1 construct used to generate the transgenic model. This demonstrates that the loss of contact inhibition is due to a direct effect of HIV-1. Therefore, proliferation induced by HIV-1 gene expression is likely to play a key role in the pathogenesis of HIVAN.