HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy
HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy
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DOI：
10.1046/j.1523-1755.2000.00152.x
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发表时间：
2000-07-01
影响因子：
19.6
通讯作者：
Klotman, PE
中科院分区：
文献类型：
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作者：
Barisoni, L;Bruggeman, LA;Klotman, PE
背景人类免疫缺陷病毒相关性肾病（HIVAN）是HIV-1血清阳性患者肾衰竭的最常见原因。最近使用HIV-1转基因小鼠模型的研究表明，HIV-1在肾脏中的表达是HIVAN发展所必需的。然而，目前尚不清楚的是负责发病机制和基本病理过程的肾细胞类型。为了解决这些问题，我们使用了转基因小鼠模型的HIV。我们确定了细胞类型在肾脏中的HIV转基因表达发生使用原位杂交。我们使用Ki-67抗体和细胞类型特异性标志物（包括WT-1、突触足蛋白、Na+，K+-ATP酶、内收蛋白和结蛋白）通过免疫细胞化学分析评估增殖证据。TUNEL法检测细胞凋亡。我们发现，肾小球和肾小管上皮细胞表达HIV-1转基因的疾病过程中早期肾结构保存良好。然而，当肾小管上皮细胞失去其分化的立方形表型时，转基因表达在肾小管上皮细胞中丢失。在肾小球上皮细胞中，发生去分化，WT-1和突触足蛋白的表达减少，与结蛋白表达的激活有关。管状微囊的形成还伴随着Na+，K+-ATP酶表达在侧部和顶部细胞膜上的错误定位。这些研究支持了肾小球和肾上皮细胞是HIV-1在肾脏中发病的主要靶点的假设。基本的病理过程是上皮细胞周期失调，增殖增加，细胞凋亡，细胞去分化和细胞极性改变。
Background. Human immunodeficiency virus-associated nephropathy (HIVAN) is the most common cause of renal failure in HIV-1-seropositive patients. Recent studies using an HIV-1 transgenic mouse model have demonstrated that expression of HIV-1 in the kidney is required for the development of HIVAN. What has remained unclear, however, is the renal cell type responsible for pathogenesis and the essential pathological process.Methods. To address these issues, we used a transgenic murine model of HIVAN. We identified the cell types in kidney in which HIV transgene expression occurs using in situ hybridization. We evaluated evidence of proliferation by immunocytochemical analysis using an antibody to Ki-67 and cell type-specific markers, including WT-1, synaptopodin, Na+,K+-ATPase, adducin, and desmin. TUNEL assay was used to evaluate apoptosis.Results. We found that glomerular and tubular epithelial cells express the HIV-1 transgene early in the disease process when renal architecture is well preserved. Transgene expression is lost, however, in tubular epithelial cells when they lose their differentiated cuboidal phenotype. In glomerular epithelial cells, dedifferentiation occurs with reduced expression of WT-1 and synaptopodin, in association with activation of desmin expression. Tubular microcysts also form with mislocalization of Na+,K+-ATPase expression to the lateral and apical cellular membranes.Conclusions. These studies support the hypothesis that the glomerular and renal epithelial cells are the primary targets of HIV-1 pathogenesis in the kidney. The essential pathologic process is dysregulation of the epithelial cell cycle with increased proliferation, apoptosis, cellular dedifferentiation, and altered cellular polarity.