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.
Highlights
The incidence of diabetes is increasing worldwide, including type 2 diabetes in women of reproductive age
This is mainly due to reduced nephron numbers and glomerular hypertrophy, which are caused by the imbalance between the nitric oxide (NO) and reactive oxygen species required for nephrogenesis [3,4]
The main findings of this study are as follows: (1) the offspring of mothers with STZ-induced diabetes had low nephron number, kidney injury, hypertension, increased Asymmetric dimethylarginine (ADMA) levels, and decreased renal arginine-to-ADMA ratio; (2) ADMA impaired nephrogenesis and reduced nephron numbers in a metanephroi culture; (3) kidney injury, increased ADMA, decreased arginineto-ADMA ratio, and decreased dimethylarginine dimethylaminohydrolase (DDAH) activity in the STZ group were reversed by maternal citrulline therapy
Summary
The incidence of diabetes is increasing worldwide, including type 2 diabetes in women of reproductive age. Evidence from human and animal studies suggests that maternal malnutrition causes developmental programming of adult kidney disease in the offspring [3,4,5,6,7,8]. This is mainly due to reduced nephron numbers and glomerular hypertrophy, which are caused by the imbalance between the nitric oxide (NO) and reactive oxygen species required for nephrogenesis [3,4]. We hypothesized that maternal diabetes causes increased ADMA and NO deficiency, resulting in kidney disease in the adult offspring that can be prevented by maternal citrulline supplementation
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