Rai Partab, Singh Tejinder, Lederman Rivka, Chawla Amrita, Kumar Dileep, Cheng Kang, Valecha Gautam, Mathieson Peter W, Saleem Moin A, Malhotra Ashwani, Singhal Pravin C
Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
Department of Medicine, Feinstein Institute for Medical Research, North Shore LIJ Medical School, NY, USA; Department of Pediatrics, University of Bristol, Bristol, UK.
Cell Signal. 2015 Mar;27(3):460-9. doi: 10.1016/j.cellsig.2014.12.011. Epub 2014 Dec 24.
In the present study, we evaluated the effect of short term hyperglycemia on renal lesions in a mouse model (Tg26) of HIV-associated nephropathy (HIVAN). Control and Tg26 mice in groups (n=6) were administered either normal saline (FVBN or Tg) or streptozotocin (FVBN+STZ or Tg26+STZ). After two weeks, biomarkers were collected and kidneys were harvested. FVBN+ STZ and Tg26+STZ displayed elevated serum glucose levels when compared to FVBN and Tg26 respectively. Tg26+STZ displayed elevated (P<0.05) blood urea nitrogen (BUN) levels (P<0.05) and enhanced (P<0.01) proteinuria when compared to Tg26. Tg26+STZ displayed enhanced (P<0.001) number of sclerotic glomeruli and microcysts vs. Tg26. Renal tissues of Tg26 displayed down regulation of vitamin D receptor (VDR) expression and enhanced Ang II production when compared to FVBN mice. Hyperglycemia exacerbated down regulation of VDR and production of Ang II in FVBN and Tg mice. Hyperglycemia increased kidney cell reactive oxygen species (ROS) production and oxidative DNA damage in both FVBN and Tg26 mice. In in vitro studies, HIV down regulated podocyte VDR expression and also enhanced renin angiotensin system activation. In addition, both glucose and HIV stimulated kidney cell ROS generation and DNA damage and compromised DNA repair; however, tempol (superoxide dismutase mimetic), losartan (Ang II blocker) and EB1089 (VDR agonist) provided protection against DNA damaging effects of glucose and HIV. These findings indicated that glucose activated the RAS and inflicted oxidative stress-mediated DNA damage via down regulation of kidney cell VDR expression in HIV milieu both in vivo and in vitro.
在本研究中，我们评估了短期高血糖对HIV相关性肾病（HIVAN）小鼠模型（Tg26）肾损伤的影响。将对照组和Tg26组小鼠（每组n = 6）分别给予生理盐水（FVBN或Tg）或链脲佐菌素（FVBN + STZ或Tg26 + STZ）。两周后，收集生物标志物并摘取肾脏。与FVBN和Tg26相比，FVBN + STZ和Tg26 + STZ的血清葡萄糖水平分别升高。与Tg26相比，Tg26 + STZ的血尿素氮（BUN）水平升高（P < 0.05），蛋白尿增加（P < 0.01）。与Tg26相比，Tg26 + STZ的硬化肾小球和微囊肿数量增加（P < 0.001）。与FVBN小鼠相比，Tg26的肾组织中维生素D受体（VDR）表达下调，血管紧张素II（Ang II）生成增加。高血糖加剧了FVBN和Tg小鼠中VDR的下调和Ang II的生成。高血糖增加了FVBN和Tg26小鼠肾细胞活性氧（ROS）的产生和氧化性DNA损伤。在体外研究中，HIV下调足细胞VDR表达，并增强肾素血管紧张素系统激活。此外，葡萄糖和HIV均刺激肾细胞ROS生成和DNA损伤，并损害DNA修复；然而，Tempol（超氧化物歧化酶模拟物）、氯沙坦（Ang II阻滞剂）和EB1089（VDR激动剂）可防止葡萄糖和HIV对DNA的损伤作用。这些发现表明，在体内和体外，葡萄糖均通过下调HIV环境中肾细胞VDR表达激活肾素血管紧张素系统（RAS），并造成氧化应激介导的DNA损伤。
