Department of Animal Science, University of Manitoba, and Integrative Biology Laboratory, St. Boniface Hospital Research Centre, 351 Tache Ave., Winnipeg, Manitoba, Canada R2H 2A6.
Am J Physiol Renal Physiol. 2011 Jan;300(1):F189-98. doi: 10.1152/ajprenal.00272.2010. Epub 2010 Oct 27.
Hyperhomocysteinemia, a condition of elevated blood homocysteine (Hcy) levels, is a metabolic disease. It is a common clinical finding in patients with chronic kidney diseases and occurs almost uniformly in patients with end-stage renal disease. Hyperhomocysteinemia is also a risk factor for cardiovascular disease. Our recent studies indicate that hyperhomocysteinemia can lead to renal injury by inducing oxidative stress. Oxidative stress is one of the important mechanisms contributing to Hcy-induced tissue injury. Folic acid supplementation is regarded as a promising approach for prevention and treatment of cardiovascular disease associated with hyperhomocysteinemia due to its Hcy-lowering effect. However, its effect on the kidney is not clear. The aim of this study was to examine the effect of folic acid supplementation on Hcy-induced superoxide anion production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the kidney during hyperhomocysteinemia. Hyperhomocysteinemia was induced in male Sprague-Dawley rats fed a high-methionine diet for 12 wk with or without folic acid supplementation. A group of rats fed a regular diet was used as control. There was a significant increase in levels of superoxide anions and lipid peroxides in kidneys isolated from hyperhomocysteinemic rats. Activation of NADPH oxidase was responsible for hyperhomocysteinemia-induced oxidative stress in the kidney. Folic acid supplementation effectively antagonized hyperhomocysteinemia-induced oxidative stress via its Hcy-lowering and Hcy-independent effect. In vitro study also showed that 5-methyltetrahydrofolate, an active form of folate, effectively reduced Hcy-induced superoxide anion production via NADPH oxidase. Xanthine oxidase activity was increased and superoxide dismutase (SOD) activity was decreased in the kidney of hyperhomocysteinemic rats, which might also contribute to an elevation of superoxide anion level in the kidney. Folic acid supplementation attenuated xanthine oxidase activity and restored SOD activity in the kidney of hyperhomocysteinemic rats. These results suggest that folic acid supplementation may offer renal protective effect against oxidative stress.
高同型半胱氨酸血症是一种血液同型半胱氨酸（Hcy）水平升高的代谢性疾病。它是慢性肾脏病患者的常见临床发现，几乎普遍存在于终末期肾病患者中。高同型半胱氨酸血症也是心血管疾病的一个危险因素。我们最近的研究表明，高同型半胱氨酸血症可通过诱导氧化应激导致肾损伤。氧化应激是导致 Hcy 诱导的组织损伤的重要机制之一。叶酸补充被认为是预防和治疗与高同型半胱氨酸血症相关的心血管疾病的有前途的方法，因为它具有降低 Hcy 的作用。然而，其对肾脏的影响尚不清楚。本研究旨在研究叶酸补充对高同型半胱氨酸血症时肾脏中通过烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶诱导的超氧阴离子产生的影响。通过给予高蛋氨酸饮食 12 周诱导雄性 Sprague-Dawley 大鼠高同型半胱氨酸血症，同时或不给予叶酸补充。一组给予常规饮食的大鼠作为对照。从高同型半胱氨酸血症大鼠分离的肾脏中超氧阴离子和脂质过氧化物水平显著增加。NADPH 氧化酶的激活是导致肾脏中高同型半胱氨酸血症诱导的氧化应激的原因。叶酸补充通过其降低 Hcy 和不依赖 Hcy 的作用有效拮抗高同型半胱氨酸血症诱导的氧化应激。体外研究还表明，叶酸的活性形式 5-甲基四氢叶酸可有效通过 NADPH 氧化酶减少 Hcy 诱导的超氧阴离子产生。黄嘌呤氧化酶活性增加，超氧化物歧化酶（SOD）活性降低，这也可能导致肾脏中超氧阴离子水平升高。叶酸补充可减轻高同型半胱氨酸血症大鼠肾脏中黄嘌呤氧化酶的活性并恢复 SOD 活性。这些结果表明，叶酸补充可能对氧化应激提供肾脏保护作用。
