Cheng Ming-Chou, Wu Ting-Hsin, Huang Li-Tung, Tain You-Lin
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Pediatr Neonatol. 2014 Jun;55(3):189-95. doi: 10.1016/j.pedneo.2013.09.005. Epub 2013 Nov 20.
Nitric oxide (NO) deficiency occurs in humans and animals with hypertension and chronic kidney disease (CKD). An inhibitor of NO synthase, N(G)-nitro-l-arginine methyl ester (L-NAME) exacerbates kidney damage in the adult spontaneously hypertensive rat (SHR). We examined whether L-NAME exacerbated hypertensive nephrosclerosis in young SHRs and whether melatonin protects SHRs against kidney damage by restoration of the asymmetric dimethylarginine (ADMA)-NO pathway.
Rats aged 4 weeks were randomly assigned into three groups (n = 10 for each group): Group 1 (control), SHRs without treatment; Group 2 (L-NAME), SHRs received L-NAME (80 mg/L) in drinking water; and Group 3 (L-NAME + melatonin), SHRs received L-NAME (80 mg/L) and 0.01% melatonin in drinking water. All rats were sacrificed at 10 weeks of age.
L-NAME exacerbates the elevation of blood pressure, renal dysfunction, and glomerular sclerosis in young SHRs. L-NAME induced an increase of ADMA and a decrease of arginine-to-ADMA ratio in the SHR kidney. Melatonin therapy prevented L-NAME-exacerbated hypertension and nephrosclerosis in young SHRs. In addition, melatonin restored L-NAME-induced reduction of dimethylarginine dimethylaminohydrolase (DDAH; ADMA-metabolizing enzymes) activity in the SHR kidney. Next, melatonin decreased renal ADMA concentrations, increased renal arginine-to-ADMA ratio, and restored NO production in L-NAME-treated young SHRs. Moreover, melatonin reduced the degree of oxidative damaged DNA product, 8-hydroxydeoxyguanosine immunostaining in L-NAME-treated SHR kidney.
Our results indicated that L-NAME/SHR is a useful model for hypertensive nephrosclerosis in young rats. The blood pressure-lowering and renoprotective effects of melatonin is due to increases of DDAH activity, decreases of ADMA, and reduction of oxidative stress in L-NAME-treated SHR kidney. Specific therapy targeting the DDAH-ADMA pathway may be a promising approach to slowing chronic kidney disease progression in children.
一氧化氮（NO）缺乏在患有高血压和慢性肾病（CKD）的人类和动物中存在。NO合酶抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME）会加剧成年自发性高血压大鼠（SHR）的肾损伤。我们研究了L-NAME是否会加剧年轻SHR的高血压性肾硬化，以及褪黑素是否通过恢复不对称二甲基精氨酸（ADMA）-NO途径来保护SHR免受肾损伤。
将4周龄的大鼠随机分为三组（每组n = 10）：第1组（对照组），未治疗的SHR；第2组（L-NAME组），饮用含L-NAME（80 mg/L）的水的SHR；第3组（L-NAME + 褪黑素组），饮用含L-NAME（80 mg/L）和0.01%褪黑素的水的SHR。所有大鼠在10周龄时处死。
L-NAME加剧了年轻SHR的血压升高、肾功能障碍和肾小球硬化。L-NAME导致SHR肾脏中ADMA增加，精氨酸与ADMA的比值降低。褪黑素治疗可预防L-NAME加剧的年轻SHR的高血压和肾硬化。此外，褪黑素恢复了L-NAME诱导的SHR肾脏中二甲基精氨酸二甲胺水解酶（DDAH；ADMA代谢酶）活性的降低。接下来，褪黑素降低了L-NAME处理的年轻SHR的肾脏ADMA浓度，增加了肾脏精氨酸与ADMA的比值，并恢复了NO生成。此外，褪黑素降低了L-NAME处理的SHR肾脏中氧化损伤的DNA产物8-羟基脱氧鸟苷的免疫染色程度。
我们的结果表明，L-NAME/SHR是年轻大鼠高血压性肾硬化的有用模型。褪黑素的降压和肾脏保护作用是由于L-NAME处理的SHR肾脏中DDAH活性增加、ADMA降低以及氧化应激减少。针对DDAH-ADMA途径的特异性治疗可能是减缓儿童慢性肾病进展的一种有前景的方法。
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