Fainberg, Hernan Pablo
(2010)
Alterations induced by juvenile obesity on the renal tissue of nutrient restricted offspring.
PhD thesis, University of Nottingham.
Abstract
Human epidemiological studies have indentified obesity as an independent risk factor for renal disease. In addition, maternal nutrient restriction (MNR) during gestation results in a series of adaptations that may predispose those offspring to obesity and hypertension. Recent reports demonstrated that obese sheep exposed to MNR during early to mid gestation have a predisposition to ectopic lipid deposition in the heart and a rise in necrotic adipocytes, which are markers of severe metabolic dysfunction. Surprisingly, in this model of MNR, the renal tissue of those offspring showed an apparent reduction in cell apoptosis. However, renal diseases associated with obesity have a slow progression and their mechanisms are not completely understood. In the light of these results, the main hypothesis of my thesis is that the renal amelioration observed in those nutrient restricted (NR) obese offspring is a product of post-injury responses, inducing scarring and others adaptations to obesity. Therefore, some of the main regulatory factors in renal and perirenal adipose tissue (PAT) development were analysed in seven-day-old and one-year-old obese sheep offspring exposed to MNR (3.5 KJ/days) from 30 to 80 gestational days (term ≈ 145 days).
At one week of age, the renal composition and gene expression showed small changes between NR offspring and those born to control mothers. However, in PAT of NR offspring, an increased in expression of the methyltransferase DNMT-1 and a decrease in mRNA abundance of IGF-2 were observed.
At six months of age, obesity onset was accompanied by raised plasma cortisol and leptin concentration in NR offspring compared to control. By one year of age, whilst plasma leptin concentration was similar between the obese groups, in the PAT of the NR offspring there was an increase in gene expression of pro-inflammatory factors and DNMT-1, suggesting advanced adipose tissue remodelling. In kidney, regardless of in utero diet, obesity induced similar amounts of oxidative stress, activation of cellular proliferative factors and collagen deposition. Although, both obese groups had equal activation of pro-apoptotic factors (e.g p-53 and Bax), renal iron and mRNA abundance of the death receptor, Fas only increased in obese offspring born to control fed mothers. A major finding in the NR kidney was increased ectopic triglyceride deposition, indicating early onset post-injury in response to sympathetic activation and lipotoxity.
The main conclusion of my thesis is that functional changes observed in the adipose tissue lead the kidney to an initial cycle of cell proliferation, apoptosis and arrest, followed by tissue remodelling, characterised by the presence of collagen. However, this adaptation to obesity is accompanied by an increase in lipid deposition in the kidney of the NR group that may be a sign of an advanced state of metabolic dysfunction.
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