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):239-249. doi: 10.1016/j.yexmp.2018.03.005. Epub 2018 Mar 31.
Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in HIV patients, which is characterized by glomerulosclerosis and renal tubular dysfunction. Aquaporin-4 (AQP-4) is a membrane bound water channel protein that plays a distinct role in water reabsorption from renal tubular fluid. It has been proven that failure of AQP-4 insertion into the renal tubular membrane leads to renal dysfunction. However, the role of AQP-4 in HIVAN is unclear. We hypothesize that impaired water reabsorption leads to renal injury in HIVAN, where AQP-4 plays a crucial role. Renal function is assessed by urinary protein and serum blood urea nitrogen (BUN). Kidneys from HIV Transgenic (TG26) mice (HIVAN animal model) were compared to wild type mice by immunostaining, immunoblotting and quantitative RT-PCR. TG26 mice had increased proteinuria and BUN. We found decreased AQP-4 levels in the renal medulla, increased endothelin-1, endothelin receptor A and reduced Sirtuin1 (SIRT-1) levels in TG26 mice. Also, oxidative and endoplasmic reticulum stress was enhanced in kidneys of TG26 mice. We provide the first evidence that AQP-4 is inhibited due to induction of HIV associated stress in the kidneys of TG26 mice which limits water reabsorption in the kidney which may be one of the cause associated with HIVAN, impairing kidney physiology. AQP-4 dysregulation in TG26 mice suggests that similar changes may occur in HIVAN patients. This work may identify new therapeutic targets to be evaluated in HIVAN.
人类免疫缺陷病毒相关性肾病（HIVAN）是 HIV 患者终末期肾病的主要原因，其特征是肾小球硬化和肾小管功能障碍。水通道蛋白-4（AQP-4）是一种膜结合水通道蛋白，在从肾小管液中重吸收水分方面发挥着独特的作用。已经证明，AQP-4 插入肾小管膜的失败会导致肾功能障碍。然而，AQP-4 在 HIVAN 中的作用尚不清楚。我们假设水重吸收的失败导致 HIVAN 中的肾脏损伤，AQP-4 在其中发挥关键作用。肾功能通过尿蛋白和血清血尿素氮（BUN）来评估。通过免疫染色、免疫印迹和定量 RT-PCR 比较 HIV 转基因（TG26）小鼠（HIVAN 动物模型）和野生型小鼠的肾脏。TG26 小鼠的蛋白尿和 BUN 增加。我们发现 TG26 小鼠肾脏髓质中的 AQP-4 水平降低，内皮素-1、内皮素受体 A 增加，Sirtuin1（SIRT-1）水平降低。此外，TG26 小鼠肾脏的氧化和内质网应激增强。我们首次提供证据表明，由于 HIV 相关应激在 TG26 小鼠肾脏中的诱导，AQP-4 受到抑制，这限制了肾脏对水的重吸收，这可能是与 HIVAN 相关的原因之一，损害了肾脏生理功能。AQP-4 在 TG26 小鼠中的失调表明，在 HIVAN 患者中可能发生类似的变化。这项工作可能确定新的治疗靶点，以在 HIVAN 中进行评估。
