Abstract

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.

LLU Discipline

Biochemistry

Department

Basic Sciences

School

School of Medicine

First Advisor

Zhang, Lubo

Second Advisor

Casiano, Carlos

Third Advisor

Ducsay, Charles A.

Fourth Advisor

Duerksen-Hughes, Penelope

Fifth Advisor

Xiao, Dalia

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2014

Date (Title Page)

6-2014

Language

English

Library of Congress/MESH Subject Headings

Brain - Growth & Development; Fetal Hypoxia; Hypoxia-Ischemia; Brain; Gene Expression Regulation - Developmental; DNA Methylation; Receptors - Glucocorticoid; Dexamethasone;

Subject - Local

Maternal hypoxia; Perinatal hypoxic-ischemic encephalopathy; Systematic asphyxia; Organogenesis

Type

Dissertation

Page Count

143

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage 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.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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