*Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Clin Sci (Lond). 2013 Feb;124(3):191-202. doi: 10.1042/CS20120330.
Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFβ (transforming growth factor β) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.
Nox（NADPH 氧化酶）衍生的 ROS（活性氧）被认为与糖尿病肾病的发展有关。在肾脏中的 Nox 同工酶中，由于其在肾脏中的丰富表达，Nox4 尤为重要。在本研究中，我们检验了 GKT136901（一种 Nox1/4 抑制剂）可预防 db/db（糖尿病）小鼠肾病发展的假设。研究了 6 组雄性小鼠（8 周龄）：（i）未治疗的对照 db/m，（ii）低剂量 GKT136901 治疗的 db/m（每天 30mg/kg 体重），（iii）高剂量 GKT136901 治疗的 db/m（每天 90mg/kg 体重），（iv）未治疗的 db/db；（v）低剂量 GKT136901 治疗的 db/db；和（vi）高剂量 GKT136901 治疗的 db/db。GKT136901 以饲料形式给药 16 周。db/db 小鼠出现高血糖、白蛋白尿和肾脏损伤（肾小球系膜扩张、肾小管萎缩和肾小球硬化），表明发生了糖尿病和肾病。GKT136901 治疗对任何组的血浆葡萄糖或血压（BP）均无影响。糖尿病小鼠的血浆和尿液 TBARS（硫代巴比妥酸反应物质）水平分别作为系统和肾脏氧化应激的标志物增加。db/db 小鼠的 Nox4 mRNA 表达增加，但 Nox2 没有增加，Nox1 在 db/db 中几乎检测不到。db/db 小鼠的抗氧化酶 SOD-1（超氧化物歧化酶 1）表达减少。db/db 肾脏中的纤连蛋白、前胶原、TGFβ（转化生长因子β）和 VCAM-1（血管细胞黏附分子 1）含量以及 ERK1/2（细胞外信号调节激酶 1/2）的磷酸化增加，而 p38MAPK（丝裂原激活蛋白激酶）和 JNK（c-Jun N-末端激酶）没有变化。治疗降低了糖尿病小鼠的白蛋白尿、TBARS 和肾脏 ERK1/2 磷酸化，并保留了肾脏结构。我们的研究结果表明，Nox1/4 抑制剂具有肾保护作用，可能是通过减少氧化损伤和降低 ERK1/2 激活。这些现象的发生与改善血糖控制无关，这表明 GKT136901 敏感靶点涉及糖尿病并发症，而不是疾病过程。
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