angiotensinogen and Malnutrition

As an underlying mechanism of antenatal maternal malnutrition-induced type 2 diabetes mellitus (T2DM), alterations in the local pancreatic renin-angiotensin system (RAS) may play a significant role. We tested the hypothesis that antenatal maternal protein deprivation (AMPD) leads to increased activity of the local pancreatic RAS, with associated hyperglycemia in the adult progeny. Mice dams were fed either control or 50% protein restricted diet (AMPD) starting one week before conception and maintained during complete gestation. Our results demonstrate low birth weight (control 1.5 ± 0.03 and AMPD 1.3 ± 0.03) and sexually dimorphic programming of the pancreatic RAS, with development of hyperglycemia only in the female mice offspring as a consequence of AMPD. No significant difference in serum insulin concentration was observed; however, AMPD was associated with increased mRNA and protein expression of angiotensinogen, renin and angiotensin-converting enzyme (ACE)-1 in male and female offspring. Of importance, mRNA and protein expression of ACE 2 and angiotensin II receptors was up-regulated only in the male offspring, as a consequence of AMPD. We conclude that sexually dimorphic programming of the pancreatic RAS expression is associated with AMPD diet-mediated development of hyperglycemia.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Glucose; Dietary Proteins; Female; Gene Expression Regulation; Infant, Low Birth Weight; Male; Malnutrition; Mice; Pancreas; Peptidyl-Dipeptidase A; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; RNA, Messenger; Sex Characteristics

Adaptive growth responses of the embryo and fetus to nutritional restraint are important in ensuring early survival, but they are implicated in the programming of hypertension. It has been demonstrated that kidney growth and nephrogenesis are each regulated by intrarenal factors, including the insulin-like growth factors, glucocorticoids, and the renin-angiotensin system. Therefore, we have investigated the impact of periconceptional undernutrition (PCUN; from approximately 6 wk before to 7 days after conception) in singleton (control, n = 18; PCUN, n = 16) and twin pregnancies (control, n = 6; PCUN, n = 5) on the renal mRNA expression of 11beta- hydroxysteroid dehydrogensase type 1 and type 2 (11beta-HSD-1 and -2), the glucocorticoid (GR), and mineralocorticoid receptors, angiotensinogen, angiotensin receptor type 1 (AT1R) and 2 (AT2R), IGF-1 and IGF-2, and IGF1R and IGF2R at approximately 55 days gestation. There was no effect of PCUN or fetal number on fetal weight on relative kidney weight at approximately day 55 of gestation. There was an inverse relationship between the relative weight of the fetal kidney at approximately day 55 and maternal weight loss during the periconceptional period in fetuses exposed to PCUN. Exposure to PCUN resulted in a higher expression of IGF1 in the fetal kidney in singleton and twin pregnancies. Being a twin resulted in higher intrarenal expression of IGF-1 and IGF-2, GR, angiotensinogen, AT1R, and AT2R mRNA at 55 days gestation. Renal 11beta-HSD-2 mRNA expression was higher in PCUN singletons, but not PCUN twins, compared with controls. Thus, there may be an adaptive response in the kidney to the early environment of a twin pregnancy, which precedes the fetal growth restriction that occurs later in pregnancy. The kidney of the twin fetus exposed to periconceptional undernutrition may also be less protected from the consequences of glucocorticoid exposure.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Angiotensinogen; Animals; Body Weight; Female; Gene Expression Regulation, Developmental; Gestational Age; Hypertension, Renal; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Kidney; Malnutrition; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Glucocorticoid; RNA, Messenger; Sheep; Twins