It is well established that exposure to adverse environments in early life including both maternal under and over-nutrition predisposes individuals to similar adverse traditionally adult onset diseases such as the metabolic syndrome. Epidemiological observations and animal models have highlighted that early life exposure to maternal under-nutrition has a detrimental effect on offspring kidney health. The prevalence of chronic kidney disease has increased rapidly in recent years, concurrently with the growing obesity epidemic. Obesity is now prevalent in all age groups within the population including women of child-bearing age. Despite this, the effect of early life exposure to maternal obesity on long-term kidney health has not been investigated in humans. Studies in animals have demonstrated that exposure to early life under-nutrition programs the offspring kidney. Offspring exposed to maternal calorie restriction or a low protein diet typically display a reduced number of nephrons and increased glomerular areas. No studies to date have investigated the effect of maternal obesity on early life kidney and glomerular morphology. To address this, as part of this thesis, kidney morphology was assessed at weaning in male mice exposed to maternal diet-induced obesity throughout gestation and lactation. There was no effect of maternal diet on the number of nephrons counted within a distinct region in the offspring kidneys. However, glomerular density was decreased and glomerular area was increased in offspring exposed to maternal obesity. Alterations in renal morphology in early life have been linked to hypertension and renal disease in adulthood in both epidemiological and animal studies. Therefore, a second aim of this thesis was to assess blood pressure, renal function and markers of renal damage in offspring exposed to maternal obesity throughout the life-course. Post-pubescent male offspring (8 weeks of age) exposed to maternal obesity displayed increased blood pressure but no signs of renal dysfunction or damage. However, by six months of age offspring exposed to maternal obesity had increased glomerulosclerosis and tubulointerstitial fibrosis. The obesity epidemic is attributed to a shift in behaviours towards consumption of energy dense foods and inactivity. In addition, evidence from human and animal studies has highlighted that exposure to maternal obesity primes offspring to prefer sugary and fatty foods and to consume more calories. As such, offspring exposed to maternal obesity are likely to encounter an obesogenic environment in later life. A third aim of this thesis was therefore to determine the effect of maternal obesity in combination with a post-weaning obesogenic diet on offspring kidney health. To address this aim, offspring either exposed to an obesogenic diet or control diet throughout pregnancy and lactation were weaned onto either an obesogenic or control diet themselves. Six month old offspring exposed to a post-weaning obesity alone displayed indices of renal dysfunction and damage including glomerulosclerosis and tubulointerstitial fibrosis. Importantly, exposure to maternal obesity exacerbated the renal fibrosis in offspring exposed to a post-weaning obesogenic diet. With the growing prevalence of maternal obesity globally, there is great interest in determining an effective intervention to prevent adverse health outcomes in exposed individuals. The Ozanne laboratory has shown that maternal exercise in obese dams during pregnancy reduces maternal serum insulin and offspring insulin to control levels, highlighting that maternal exercise may be a promising intervention to limit adult-onset diseases in offspring exposed to early life obesity. The final aim of this thesis was to therefore assess the effect of exercise during an obese pregnancy on markers of offspring renal development during late gestation. Gene markers of ureteric bud branching, an important precursor of nephrogenesis, were increased in fetuses exposed to maternal obesity with exercise as opposed to obesity alone. Additionally one of these gene markers correlated negatively with maternal insulin levels. Protein markers indicative of an active ureteric bud branching pathway were also increased in offspring exposed to maternal obesity with exercise. In conclusion, studies conducted in this thesis demonstrate that offspring exposed to maternal obesity show alterations in renal morphology in early life and are predisposed for renal disease in later life, especially when they are challenged with a post-weaning obesogenic diet. Maternal exercise might be an effective intervention to rescue offspring renal morphology and later life health associated with maternal obesity, however this requires further investigation. These results have important implications for future generations within the setting of an ever increasing obesity epidemic and a growing prevalence of chronic kidney diseases.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:744870 |
| Date | January 2018 |
| Creators | Pinnock, Adele Grace |
| Contributors | Ozanne, Susan ; Giussani, Dino |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/276135 |
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