World Institute of Kimchi, Korea Food Research Institute, Gyeonggi-do, Republic of Korea.
J Pharmacol Exp Ther. 2011 Jun;337(3):583-90. doi: 10.1124/jpet.110.175828. Epub 2011 Feb 25.
The Imai rat is a model of spontaneous focal glomerulosclerosis, which leads to heavy proteinuria, hyperlipidemia, hypertension, and progressive renal failure. Treatment with AT1 blockers (ARBs) ameliorates proteinuria, hyperlipidemia, and nephropathy in this model. Progression of renal disease in 5/6 nephrectomized rats is associated with activation of the intrarenal angiotensin system, up-regulation of the oxidative, inflammatory, and fibrogenic pathways, and impaired activity of nuclear factor-erythroid-2-related factor 2 (Nrf2), the master regulator of genes encoding antioxidant molecules. We hypothesized that progressive nephropathy in the Imai rat is accompanied by oxidative stress, inflammation, and impaired Nrf2 activation and that amelioration of nephropathy with AT1 receptor blockade in this model may be associated with the reversal of these abnormalities. Ten-week-old Imai rats were randomized to the ARB-treated (olmesartan, 10 mg/kg/day for 24 weeks) or vehicle-treated groups. Sprague-Dawley rats served as controls. At 34 weeks of age Imai rats showed heavy proteinuria, hypoalbuminemia, hypertension, azotemia, glomerulosclerosis, tubulointerstitial inflammation, increased angiotensin II expressing cell population, up-regulations of AT1 receptor, AT2 receptor, NAD(P)H oxidase, and inflammatory mediators, activation of nuclear factor-κB and reduction of Nrf2 activity and expression of its downstream gene products in the renal cortex. ARB therapy prevented nephropathy, suppressed oxidative stress and inflammation, and restored Nrf2 activation and expression of the antioxidant enzymes. Thus progressive focal glomerulosclerosis in the Imai rats is associated with oxidative stress, inflammation, and impaired Nrf2 activation. These abnormalities are accompanied by activation of intrarenal angiotensin system and can be prevented by ARB administration.
Imai 大鼠是自发性局灶性肾小球硬化的模型动物，会导致大量蛋白尿、高血脂、高血压和进行性肾衰竭。在该模型中，使用 AT1 受体阻滞剂（ARB）治疗可改善蛋白尿、高血脂和肾病。5/6 肾切除大鼠的肾病进展与肾内血管紧张素系统的激活、氧化、炎症和纤维化途径的上调以及核因子-红细胞 2 相关因子 2（Nrf2）的活性受损有关，Nrf2 是编码抗氧化分子的基因的主要调节因子。我们假设 Imai 大鼠的进行性肾病伴随着氧化应激、炎症和 Nrf2 激活受损，并且在该模型中使用 AT1 受体阻断治疗改善肾病可能与这些异常的逆转有关。将 10 周龄的 Imai 大鼠随机分为 ARB 治疗组（奥美沙坦，10mg/kg/天，治疗 24 周）或对照组。Sprague-Dawley 大鼠作为对照组。在 34 周龄时，Imai 大鼠表现出大量蛋白尿、低白蛋白血症、高血压、氮血症、肾小球硬化、肾小管间质炎症、血管紧张素 II 表达细胞群体增加、AT1 受体、AT2 受体、NAD(P)H 氧化酶和炎症介质的上调、核因子-κB 的激活以及 Nrf2 活性和其下游基因产物在肾皮质中的表达降低。ARB 治疗预防了肾病，抑制了氧化应激和炎症，并恢复了 Nrf2 激活和抗氧化酶的表达。因此，Imai 大鼠进行性局灶性肾小球硬化与氧化应激、炎症和 Nrf2 激活受损有关。这些异常伴随着肾内血管紧张素系统的激活，可通过 ARB 给药来预防。
