Maternal citrulline supplementation prevents prenatal dexamethasone-induced programmed hypertension

Abstract

Glucocorticoids are administered to premature infants to accelerate pulmonary maturation. In experimental model, prenatal dexamethasone (DEX) results in reduced nephron number and adulthood hypertension. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), can cause oxidative stress and is involved in the development of hypertension. L-citrulline can be converted to l-arginine (the substrate for NOS) in the body. Thus we intended to determine if maternal L-citrulline therapy can prevent prenatal DEX-induced programmed hypertension by restoration ADMA/nitric oxide (NO) balance, alterations of renin-angiotensin system (RAS) and sodium transporters, and epigenetic regulation by histone deacetylases (HDACs). Male offspring were assigned to four groups: control, pregnancy rats received intraperitoneal DEX (0.2 mg/kg body weight) daily on gestational days 15 and 16 (DEX), pregnancy rats received 0.25% L-citrulline in drinking water during the entire pregnancy and lactation period (CIT), and DEX + CIT. We found DEX group developed hypertension at 16 weeks of age, which was prevented by maternal L-citrulline therapy. Prenatal DEX exposure increased plasma ADMA concentrations and reduced renal NO production. However, L-citrulline reduced plasma ADMA level and increased renal level of NO in DEX + CIT group. Next, prenatal DEX-induced programmed hypertension is related to increased mRNA expression of angiotensin and angiotensin II type 1 receptor, and class I HDACs in the kidney. Prenatal DEX exposure increased renal protein abundance of Na(+)/Cl(-) cotransporter (NCC), which was prevented by L-citrulline therapy. The beneficial effects of L-citrulline therapy include restoration of ADMA/NO balance and alteration of NCC, to prevent the prenatal DEX-induced programmed hypertension.

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.…”

“…Thus, thrifty phenotype hypothesis and catch-up growth [25] might not be major mechanisms to interpret the renal programming in this model. Some particular candidate genes/pathways related to the programmed hypertension have been studied in different models of developmental programming, such as genes for nephrogenesis, oxidative stress, RAS and epigenetic regulation [2][3][4][5][6][7][8][9][10][11]. As an attempt to elucidate the impact of these candidate genes/pathways on HF-induced renal programming, we used our NGS dataset to analyze these specific groups of genes.…”

“…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].…”

Prenatal dexamethasone-induced programmed hypertension and renal programming

“…Although glucocorticoids are recommended in women at risk of preterm labor to accelerate fetal lung maturation [5], emerging evidence indicates that antenatal glucocorticoids may elicit fetal programming that leads to hypertension in adulthood [6][7][8][9][10][11].…”

Thiazide-sensitive Na<sup>+</sup>–Cl<sup>−</sup> cotransporter: genetic polymorphisms and human diseases

“…TSC is the target of thiazide diuretics that have been most widely used as first line drugs for the treatment of hypertension in the clinic [34,35]. Recent studies showed that TSC was regulated by prenatal dexamethasone (DEX), a type of adrenocorticosteroids, and could become a new target to prevent the prenatal DEX-induced programmed hypertension by L-citrulline therapy [82].…”