Institute of Human Virology, University of Maryland, Baltimore, MD, United States.
Department of Neurology, University of Maryland, Baltimore, MD, United States.
Exp Mol Pathol. 2018 Jun;104(3):175-189. doi: 10.1016/j.yexmp.2018.03.004. Epub 2018 Mar 31.
HIV-associated nephropathy (HIVAN) is an AIDs-related disease of the kidney. HIVAN is characterized by severe proteinuria, podocyte hyperplasia, collapse, glomerular, and tubulointerstitial damage. HIV-1 transgenic (Tg26) mouse is the most popular model to study the HIV manifestations that develop similar renal presentations as HIVAN. Viral proteins, including Tat, Nef, and Vpr play a significant role in renal cell damage. It has been shown that mitochondrial changes are involved in several kidney diseases, and therefore, mitochondrial dysfunction may be implicated in the pathology of HIVAN. In the present study, we investigated the changes of mitochondrial homeostasis, biogenesis, dynamics, mitophagy, and examined the role of reactive oxygen species (ROS) generation and apoptosis in the Tg26 mouse model. The Tg26 mice showed significant impairment of kidney function, which was accompanied by increased blood urea nitrogen (BUN), creatinine and protein urea level. In addition, histological, western blot and PCR analysis of the Tg26 mice kidneys showed a downregulation of NAMPT, SIRT1, and SIRT3 expressions levels. Furthermore, the kidney of the Tg26 mice showed a downregulation of PGC1α, MFN2, and PARKIN, which are coupled with decrease of mitochondrial biogenesis, imbalance of mitochondrial dynamics, and downregulation of mitophagy, respectively. Furthermore, our results indicate that mitochondrial dysfunction were associated with ER stress, ROS generation and apoptosis. These results strongly suggest that the impaired mitochondrial morphology, homeostasis, and function associated with HIVAN. These findings indicated that a new insight on pathological mechanism associated with mitochondrial changes in HIVAN and a potential therapeutic target.
HIV 相关性肾病（HIVAN）是一种与艾滋病相关的肾脏疾病。HIVAN 的特征是严重蛋白尿、足细胞增生、塌陷、肾小球和肾小管间质损伤。HIV-1 转基因（Tg26）小鼠是研究 HIV 表现的最流行模型，其表现出与 HIVAN 相似的肾脏表现。病毒蛋白，包括 Tat、Nef 和 Vpr，在肾细胞损伤中起重要作用。已经表明，线粒体变化涉及几种肾脏疾病，因此，线粒体功能障碍可能与 HIVAN 的病理学有关。在本研究中，我们研究了线粒体动态平衡、生物发生、动力学、自噬的变化，并检查了活性氧（ROS）生成和细胞凋亡在 Tg26 小鼠模型中的作用。Tg26 小鼠表现出明显的肾功能障碍，伴有血尿素氮（BUN）、肌酐和蛋白质尿水平升高。此外，Tg26 小鼠肾脏的组织学、western blot 和 PCR 分析显示 NAMPT、SIRT1 和 SIRT3 的表达水平下调。此外，Tg26 小鼠的肾脏还表现出 PGC1α、MFN2 和 PARKIN 的下调，这与线粒体生物发生减少、线粒体动力学失衡和自噬下调分别相关。此外，我们的结果表明，线粒体功能障碍与内质网应激、ROS 生成和细胞凋亡有关。这些结果强烈表明，与 HIVAN 相关的线粒体形态、动态平衡和功能受损。这些发现表明，对与 HIVAN 中线粒体变化相关的病理机制有了新的认识，并为潜在的治疗靶点提供了依据。
