Effect of Maternal Hypoxia on Fetal Development: Programming of HIE Phenotype in Neonatal Rat Brain

<p>Developmental programming of health and disease correlates the adverse intrauterine environment and the risk of disease later in life as cardiovascular disease, metabolic diseases, renal dysfunction or neurobehavioral disorders among others. Maternal hypoxia is one of the most common intrauterine growth restricted environment during pregnancy. Perinatal hypoxic-ischemic encephalopathy is an important cause of brain injury in the newborn due to a systematic asphyxia. Our study aims to test the hypothesis that maternal hypoxia affect the organogenesis of the kidney by affecting the kidney structure and focusing on the roles of AT1R and AT2R, while the brain development will also be affected by this maternal insult increasing the vulnerability of this to HIE brain injury and the role of GR and the epigenetic modification that regulate the expression of the GR will be assessed. Finally, the MAPK/ERK pathway as part of the downstream of the neuroprotective mechanism of the GR against neonate HIE brain injury will be evaluated. To address these issues two rats model were established: perinatal hypoxia exposure model in time-dated pregnant rats and hypoxic-ischemic encephalopathy in 10-day-old rat pups. Through these studies we found that maternal hypoxia decrease the number of glomeruli in offspring rat kidneys and a down-regulation on the expression of AT1R was observed in the kidneys of the adult rats in a sex dimorphism way, affecting more the females than the males. In addition, we observed that maternal hypoxia increased the vulnerability of the brain to HIE on P-10 pups by repressing the expression of GR. Epigenetics studies demonstrated that this down-regulation of GR was due to hypermethylation on promoter region of exon variants 17 and 111 of the GR gene. Dexamethasone, a synthetic glucocorticoid, treatment on normoxic P-10 brains increased the expression of LPGDS, and pERK44 and also the level of prostaglandin D2, while, the neuroprotective effect of dexamethasone observed against HIE brain injury on P-10 pups was diminished by MAPK/ERK and LPGDS inhibitor, and by blocking the DP1 receptor. These findings provide a new insight in understanding the pathogenesis of HIE in newborns and may suggest potential targets for the prevention and treatment of HIE brain injury.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Basic Sciences

Year

2014

Author dc:creator

• Gonzalez-Rodriguez, Pablo J

Contributors dc:contributor

• Zhang, Lubo
• Casiano, Carlos
• Ducsay, Charles A.
• Duerksen-Hughes, Penelope
• Xiao, Dalia

• Biochemistry
• Life Sciences
• Medicine and Health Sciences
• Brain - Growth & Development; Fetal Hypoxia; Hypoxia-Ischemia; Brain; Gene Expression Regulation - Developmental; DNA Methylation; Receptors - Glucocorticoid; Dexamethasone;
• Maternal hypoxia; Perinatal hypoxic-ischemic encephalopathy; Systematic asphyxia; Organogenesis

Statement dc:rights

• This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/204

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-1195