Brain renin-angiotensin system: fetal epigenetic programming by maternal protein restriction during pregnancy.
OBJECTIVE
Maternal protein malnutrition during pregnancy can lead to significant alterations in the systemic renin-angiotensin system (RAS) in the fetus. All components of the RAS are present in brain and may be altered in many disease states. Importantly, these disorders are reported to be of higher incidence in prenatally malnourished individuals. In the current study, we tested the hypothesis that antenatal maternal low protein diet (MLPD) leads to epigenetic changes and alterations in gene expression of brain RAS of the mouse fetus.


METHODS
Mice dams were given control and 50% MLPD during second half of the gestation. We analyzed messenger RNA (mRNA), microRNA (miRNA), promoter DNA methylation, and protein expression of various RAS genes in the fetal offspring.


RESULTS
As a consequence of 50% MLPD, fetal brains showed increased mRNA expression of angiotensinogen and angiotensin converting enzyme-1 (ACE-1), with a decrease in mRNA levels of angiotensin II type-2 (AT2) receptors. In contrast, while angiotensinogen protein expression was unaltered, the protein levels of ACE-1 and AT2 receptor genes were significantly reduced in the fetal brain from the MLPD dams. Our results also demonstrated hypomethylation of the CpG islands in the promoter regions of ACE-1 gene, and upregulation of the miRNAs, mmu-mir-27a and 27b, which regulate ACE-1 mRNA translation. Furthermore, our study showed reduced expression of the miRNA mmu-mir-330, which putatively regulates AT2 translation.


CONCLUSIONS
For the developing fetal brain RAS, MLPD leads to significant alterations in the mRNA and protein expression, with changes in DNA methylation and miRNA, key regulators of hypertension in adults.
Goyal
Ravi
R
Center for Perinatal Biology, Department of Physiology, School of Medicine, Loma Linda University, Loma Linda, California 92350, USA.
Goyal
Dipali
D
Leitzke
Arthur
A
Gheorghe
Ciprian P
CP
Longo
Lawrence D
LD
D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism; D001923:Brain Chemistry; D019175:DNA Methylation; D018753:Diet, Protein-Restricted; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D005333:Fetus / Q000378:metabolism; D015870:Gene Expression; D005865:Gestational Age; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D035683:MicroRNAs / Q000032:analysis; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011247:Pregnancy; D011248:Pregnancy Complications; D011401:Promoter Regions, Genetic / Q000235:genetics; D011488:Protein Deficiency / Q000150:complications*; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics* / Q000502:physiology
D035683:MicroRNAs; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A