Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Hypertens Res. 2013 Apr;36(4):361-7. doi: 10.1038/hr.2012.204. Epub 2013 Jan 31.
One major precursor of carbonyl stress, methylglyoxal (MG), is elevated in the plasma of chronic kidney disease (CKD) patients, and this precursor contributes to the progression of vascular injury, hypertension and renal injury in diabetic nephropathy patients. This molecule induces salt-sensitive hypertension via a reactive oxygen species-mediated pathway. We examined the role of MG in the pathogenesis of hypertension and cardio-renal injury in Dahl salt-sensitive (Dahl S) rats, which is a rat model of CKD. Nine-week-old Dahl S rats were fed a 1% NaCl diet, and 1% MG was added to their drinking water for up to 12 weeks. Blood pressure and cardio-renal injuries were compared with rats treated with tap water alone. The angiotensin II receptor blocker (ARB), candesartan (10 mg kg(-1) day(-1)), was administered to MG Dahl S rats to determine the impact of this drug on the pathogenesis of MG-induced CKD. A progressive increase in systolic blood pressure was observed (123±1-148±5 mm Hg) after 12 weeks of MG administration. MG administration significantly increased urinary albumin excretion, glomerular sclerosis, tubular injury, myocardial collagen content and cardiac perivascular fibrosis. MG also enhanced the renal expression of Nɛ-carboxyethyl-lysine (an advanced glycation end product), 8-hydroxydeoxyguanosine (a marker of oxidative stress), macrophage (ED-1) positive cells (a marker of inflammation) and nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity. Candesartan treatment for 4 weeks significantly reduced these parameters. These results suggest that MG-induced hypertension and cardio-renal injury and increased inflammation and carbonyl and oxidative stress, which were partially preventable by an ARB.
羰基应激的一个主要前体物甲基乙二醛（MG）在慢性肾脏病（CKD）患者的血浆中升高，并且该前体物有助于糖尿病肾病患者血管损伤、高血压和肾脏损伤的进展。这种分子通过活性氧物质介导的途径诱导盐敏感性高血压。我们研究了 MG 在 Dahl 盐敏感（Dahl S）大鼠高血压和心肾损伤发病机制中的作用，Dahl S 大鼠是 CKD 的大鼠模型。9 周龄的 Dahl S 大鼠给予 1%NaCl 饮食，并在饮用水中添加 1%MG 长达 12 周。与单独用自来水处理的大鼠相比，比较了血压和心肾损伤。给予血管紧张素 II 受体阻滞剂（ARB）坎地沙坦（10mg/kg/d）给 MG Dahl S 大鼠，以确定该药物对 MG 诱导的 CKD 发病机制的影响。MG 给药 12 周后观察到收缩压逐渐升高（123±1-148±5mmHg）。MG 给药显著增加尿白蛋白排泄、肾小球硬化、肾小管损伤、心肌胶原含量和心脏血管周围纤维化。MG 还增强了肾脏中 Nɛ-羧乙基赖氨酸（一种糖基化终产物）、8-羟基脱氧鸟苷（氧化应激标志物）、巨噬细胞（ED-1）阳性细胞（炎症标志物）和烟酰胺腺嘌呤二核苷酸磷酸（NAD（P）H）氧化酶活性的表达。坎地沙坦治疗 4 周可显著降低这些参数。这些结果表明，MG 诱导的高血压和心肾损伤以及炎症和羰基及氧化应激的增加，可部分被 ARB 预防。
