Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
PLoS One. 2013;8(2):e55420. doi: 10.1371/journal.pone.0055420. Epub 2013 Feb 7.
Diabetes mellitus complicates pregnancies, leading to diseases in adult life in the offspring. Asymmetric dimethylarginine (ADMA) is increased in diabetes mellitus, kidney disease, and hypertension. We tested whether maternal diabetes causes increased ADMA in rats, resulting in kidney disease and hypertension in the adult offspring, and whether these can be prevented by maternal citrulline supplementation. Newborn female and pregnant Sprague-Dawley rats were injected with streptozotocin (STZ), which made up the nSTZ and STZ models, respectively. For the STZ model, 4 groups of male offspring were killed at age 3 months: the control, STZ, and Cit and STZ+Cit (control and STZ rats treated with 0.25% l-citrulline solution, respectively) groups. The nSTZ rats had lower nephron numbers. The renal level of ADMA was higher in the nSTZ rats than in controls. The STZ group developed kidney injury, renal hypertrophy, and elevated blood pressure at the age of 12 weeks. These conditions were found to be associated with increased ADMA levels, decreased nitric oxide (NO) production, and decreased dimethylarginine dimethylaminohydrolase (DDAH) activity in the kidney. In addition, ADMA caused a nephron deficit in cultured rat metanephroi. Maternal citrulline supplementation prevented hypertension and kidney injury, increased the renal DDAH-2 protein level, and restored the levels of ADMA and NO in the STZ+Cit group. Reduced nephron number and increased ADMA contribute to adult kidney disease and hypertension in offspring of mothers with STZ-induced diabetes. Manipulation of the ADMA-NO pathway by citrulline supplementation may be a potential approach to prevent these conditions.
糖尿病会使妊娠复杂化，导致后代在成年后患相关疾病。非对称性二甲基精氨酸（ADMA）在糖尿病、肾病和高血压中增加。我们检测了母体糖尿病是否会导致大鼠 ADMA 增加，进而导致成年后代的肾病和高血压，以及母体补充瓜氨酸是否可以预防这些情况。新生雌性和妊娠 Sprague-Dawley 大鼠分别注射链脲佐菌素（STZ），分别构成 nSTZ 和 STZ 模型。对于 STZ 模型，3 月龄时处死 4 组雄性后代：对照组、STZ 组、Cit 和 STZ+Cit（分别用 0.25% l-瓜氨酸溶液处理对照组和 STZ 大鼠）组。nSTZ 大鼠的肾单位数量减少。nSTZ 大鼠的肾 ADMA 水平高于对照组。STZ 组在 12 周龄时出现肾损伤、肾肥大和血压升高。这些情况与 ADMA 水平升高、一氧化氮（NO）产生减少和肾中二甲基精氨酸二甲氨基水解酶（DDAH）活性降低有关。此外，ADMA 在培养的大鼠后肾原基中引起肾单位缺失。母体瓜氨酸补充可预防高血压和肾损伤，增加肾 DDAH-2 蛋白水平，并恢复 STZ+Cit 组的 ADMA 和 NO 水平。减少的肾单位数量和增加的 ADMA 导致母亲 STZ 诱导的糖尿病后代成年期的肾病和高血压。通过瓜氨酸补充来操纵 ADMA-NO 途径可能是预防这些情况的一种潜在方法。
