Effects of maternal l-citrulline supplementation on renal function and blood pressure in offspring exposed to maternal caloric restriction: The impact of nitric oxide pathway

Maternal undernutrition can cause reduced nephron number and glomerular hypertrophy, consequently leading to adult kidney disease. We intended to elucidate whether NO deficiency evolves to kidney disease vulnerability in offspring from mothers with caloric restriction diets and whether maternal l-citrulline (l-Cit) supplementation can prevent this. Using a rat model with 50% caloric restriction, four groups of 3-month-old male offspring were sacrificed to determine their renal outcome: control, caloric restriction (CR), control treated with 0.25% l-citrulline solution during the whole period of pregnancy and lactation (Cit), and CR treated in the same way (CR + Cit group). The CR group had low nephron numbers, increased glomerular diameter, and an increased plasma creatinine level compared with the control group. Maternal l-Cit supplementation prevented these effects. The CR + Cit and Cit groups developed hypertension beginning at 4 and 8 weeks of age, respectively. Plasma asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels were increased, but l-arginine/ADMA ratios (AAR) were decreased in the CR group vs the control group. This was prevented by maternal l-Cit supplementation. Renal cortical neuronal NOS-α (nNOSα) protein abundance was significantly decreased in the Cit and CR + Cit groups. Collectively, reduced nephron number, reduced renal nNOSα expression, increased ADMA, and decreased AAR contribute to the developmental programming of adult kidney disease and hypertension. Although maternal l-Cit supplementation prevents caloric restriction-induced low nephron number and renal dysfunction, it also induces hypertension.