Programming of fetal cardio-renal mitochondria by maternal nutrition

Bibliographic Details
Main Author: Pereira, Susana Patrícia da Silva
Publication Date: 2016
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: https://hdl.handle.net/10316/29635
Summary: Tese de doutoramento em Biociências, na especialidade de Toxicologia, apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra
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spelling Programming of fetal cardio-renal mitochondria by maternal nutritionfetal programmingfetal under-nutritionmetabolic diseasebaboonheartkidneyTese de doutoramento em Biociências, na especialidade de Toxicologia, apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de CoimbraEarly-life malnutrition results in structural alterations to fetal kidney and heart, predisposing offspring to later life cardio-renal dysfunction. Epidemiologic studies link low birth weight to predisposition to cardiovascular disease (CVD) later in life with both sex and diet impacting the incidence of CVD. Kidneys of adults who suffered from growth restriction at birth have substantial variation in nephron endowment. Animal models suggest cardio-renal structural and functional consequences in the offspring exposed to sub-optimal intrauterine nutrition. Mitochondrial bioenergetics plays a key role in cardiac and renal energy metabolism, growth and function. In this relevant work, we hypothesized that moderate maternal nutrient reduction (MNR) would adversely impact fetal cardio-renal mitochondrial metabolism in a well-established non-human primate model which produces intra-uterine growth reduction at term. Female pregnant baboons were fed normal chow diet or 70% of control diet (maternal nutrient reduction, MNR). Cesarean sections were performed at 0.9 gestation (165 days gestation) under anesthesia. Maternal fasting blood was drawn from the femoral vein in the morning before cesarean section and before the fetus was exteriorized from the uterine cavity. Umbilical vein blood was also sampled. The mother, the placenta and the fetus were analyzed for morphometric measurements and tissue sampling. Fetal kidneys and heart were rapidly harvested and appropriately processed, flash frozen or fixed, for posterior analyses. Biochemical and amino acid analyses were performed in the maternal and fetal blood samples. Analysis of mitochondrial DNA was performed by quantitative real-time PCR, and Human Mitochondrial Energy Metabolism and Human Mitochondria Pathway PCR Arrays were used to analyze mitochondrial relevant mRNA. In situ protein content was detected by immunohistochemistry and semi-quantification was performed by Western blot. Enzymatic activity of mitochondrial proteins was determined by alterations in the absorbance of specific substrates or products. Adenine nucleotide levels and energy charge were determined by HPLC, as well determination of vitamin E and reduced and oxidized glutathione contents. Other indicators of oxidative state, as malondialdehyde content (MDA), glutathione peroxidase and glutathione reductase activities were determined spectrophotometrically. Ultimately, transmission electron microscopy was use to assess mitochondrial morphology. MNR until 0.9 gestation decreases maternal weight gain and placental weight, being the effects more severe in MNR mothers carrying a male fetuses. Despite the smaller overall fetal size, fetal kidney weight-to-body weight or the heart weight-to-body weight ratios were not affected. MNR caused adjustments in the protein metabolism reflected in altered maternal amino acids concentrations and impaired glucose metabolism, with MNR mothers displaying higher levels of cortisol and glucose in blood circulation. Regarding the fetal kidney, we demonstrated fetal gender-specific differential mRNA expression encoding mitochondrial metabolite transport and dynamics proteins. MNR-related differential gene expression was more evident in female fetuses, with 16 transcripts significantly altered, including 14 downregulated and 2 upregulated. MNR impacted 10 transcripts in male fetuses, with 7 downregulated and 3 upregulated. Alteration in mRNA levels was accompanied by a decrease in mitochondrial protein cytochrome c oxidase subunit VIc. In conclusion, transcripts encoding fetal renal mitochondrial energy metabolism proteins are nutrition sensitive in a gender-dependent manner. For the fetal cardiac left ventricle, we found that MNR increased mtDNA content and the transcription of key mitochondrial genes involved in mitochondrial dynamics and oxidative phosphorylation (OXPHOS), resulting in increased content of several mitochondrial proteins, namely components of the mitochondrial respiratory chain (NDUFB8, UQCRC1 and cytochrome c) and ATP synthase. However, the activity of OXPHOS enzymes was significantly decreased in MNR fetuses, possibly contributing to a decreased ATP content and an increased oxidative stress in the cardiac left ventricle tissues reported by augmented levels of the lipid peroxidation marker, MDA. Microscopy of the fetal cardiac left ventricles reflected the disturbance induced by MNR, revealing mitochondria with sparse and disarranged cristae. These checkpoints suggest that MNR orchestrated a serial of events that ultimately resulted in an impaired capacity of fetal cardiac left ventricle tissue to produce energy through the OXPHOS system. The present study provides for the first time evidence of an association between MNR and mitochondrial remodeling in the fetus. Although the MNR fetal manifestation were tissue and gender specific, the overall scenario point to and impairment in mitochondrial function in the fetal tissues analyzed. We speculate that these differences lead to decreased mitochondrial fitness that contributes to cardio-renal dysfunction in later life. Our work has a translational application in human health, showing that control of maternal health during pregnancy may reduce long term disease risk in the offspring with greatest benefit for the individual and for national health care systems.FCT - SFRH/BD/64694/20092016-03-16doctoral thesisinfo:eu-repo/semantics/publishedVersionhttps://hdl.handle.net/10316/29635https://hdl.handle.net/10316/29635TID:101320272engPereira, Susana Patrícia da Silvainfo:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2021-09-30T08:49:33Zoai:estudogeral.uc.pt:10316/29635Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T05:16:26.680670Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Programming of fetal cardio-renal mitochondria by maternal nutrition
title Programming of fetal cardio-renal mitochondria by maternal nutrition
spellingShingle Programming of fetal cardio-renal mitochondria by maternal nutrition
Pereira, Susana Patrícia da Silva
fetal programming
fetal under-nutrition
metabolic disease
baboon
heart
kidney
title_short Programming of fetal cardio-renal mitochondria by maternal nutrition
title_full Programming of fetal cardio-renal mitochondria by maternal nutrition
title_fullStr Programming of fetal cardio-renal mitochondria by maternal nutrition
title_full_unstemmed Programming of fetal cardio-renal mitochondria by maternal nutrition
title_sort Programming of fetal cardio-renal mitochondria by maternal nutrition
author Pereira, Susana Patrícia da Silva
author_facet Pereira, Susana Patrícia da Silva
author_role author
dc.contributor.author.fl_str_mv Pereira, Susana Patrícia da Silva
dc.subject.por.fl_str_mv fetal programming
fetal under-nutrition
metabolic disease
baboon
heart
kidney
topic fetal programming
fetal under-nutrition
metabolic disease
baboon
heart
kidney
description Tese de doutoramento em Biociências, na especialidade de Toxicologia, apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra
publishDate 2016
dc.date.none.fl_str_mv 2016-03-16
dc.type.driver.fl_str_mv doctoral thesis
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://hdl.handle.net/10316/29635
https://hdl.handle.net/10316/29635
TID:101320272
url https://hdl.handle.net/10316/29635
identifier_str_mv TID:101320272
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
_version_ 1833602303482920960

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