Asymmetric Dimethylarginine Is Associated with Developmental Programming of Adult Kidney Disease and Hypertension in Offspring of Streptozotocin-Treated Mothers

Abstract

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.

Maternal fructose-intake-induced renal programming in adult male offspring

“…We also reported that ADMAinduced NO/reactive oxygen species (ROS) imbalance is involved in the development of hypertension in several programming models [6][7][8][9][10]. As shown in Table 2, plasma levels of L-citrulline, L-arginine and ADMA and L-arginine-to-ADMA ratio were not different between control and HF group at both 3 weeks and 3 months of age.…”

“…We recently observed that renal programming and hypertension developed in the adult male offspring of mother rats exposed to caloric restriction [6,7], diabetes [8], dexamethasone treatment [9,10] and high-fructose (HF) diet [11]. A number of mechanisms, including glucocorticoid effects, oxidative stress, epigenetic regulation, alterations of renin-angiotensin system (RAS), impaired tubular sodium handling and reduction in nephron numbers, have been put forward to interpret renal programming [2][3][4].…”

Aliskiren in early postnatal life prevents hypertension and reduces asymmetric dimethylarginine in offspring exposed to maternal caloric restriction

“…We found that aliskiren therapy decreased ADMA levels but increased the ratio of l-arginine to ADMA in the plasma, which was consistent with our recent findings showing that ADMA contributed to programmed hypertension and that aliskiren had an ADMA-lowering effect. 5,12 Unlike aliskiren, losartan decreases BP but not ADMA: compared with aliskiren, its BP-lowering effect is similar. However, losartan had no effects on ADMA and NO bioavailability (represented by the ratio of l-arginine to ADMA and NOx) in this study.…”

“…5 Kidney homogenate was prepared, and 10 μg of protein was added to 1 mM CPH and 0.1 mM diethylenetriaminepentaacetic acid in a total volume of 100 μl of Chelex-treated PBS. Samples were placed in a 50μl glass capillary (Wilmad Glass, Buena, New Jersey, USA).…”

“…[3][4][5] ADMA can reduce the synthesis of NO while inducing superoxide production. Thus, ADMA levels tightly regulate NO/ROS balance.…”