Proceedings of The Physiological Society
University College Dublin (2009) Proc Physiol Soc 15, C96
In-utero nutritional programming of kidney development and its long term impact on renal oxidative stress following juvenile obesity
H. P. Fainberg1, D. S. Gardner2, K. D. Sinclair3, H. Budge1, M. E. Symonds1
1. Centre for Reproduction and Early Life, Institute of Clinical Science, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom. 2. School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom. 3. School of Biosciences, University of Nottingham, Nottingham, United Kingdom.
Maternal nutrient restriction, coincident with early fetal kidney development, can increase glucocorticoid action in the newborn kidney1. Fetal adaptations in the kidney may also determine the long term consequences following juvenile obesity and the onset of hypertension. One important mechanism implicated in both obesity and renal disease is enhanced oxidative stress, leading to glomerulosclerosis. Two key regulators of this process are the angiogenic hypoxia inducible factor (HIF)-1α and the pro-apoptotic receptor Fas. The present study, therefore, examined how the early in-utero diet results in renal adaptations to oxidative stress induced by juvenile obesity. Pregnant sheep (n=26) were randomly assigned to a normal (7 MJ/day) or nutrient restricted diet (NR, 3.5 MJ/day), from 30-80 days of gestation (term = 147 days) and fed to requirements at all other times. After weaning, the NR (NR-O, n=11) and obese (O, n=7) offspring were reared in an obesogenic environment to promote fat deposition. The lean group (L, n=8) remained out to pasture. At one year of age, all sheep underwent measurements of plasma cysteine concentration and were then humanely euthanased with kidneys sampled for renal malondialdehyde (MDA) concentrations and real-time gene expression of the Fas and HIF-1α genes. Obesity raised the total plasma cysteine (L 12.8±1.1; O 18.3±1; NR-O 18±1.6 (p<0.05)) and intra-renal (i.e. MDA) oxidative stress in both obese groups. In addition, although gene expression of HIF-1α also increased with obesity, this response was amplified in offspring born to NR mothers (L 1±0.285; O 1.964±0.552; NR-O 5.353 ±1.025 2-(ΔCT) (p<0.05)), whereas mRNA abundance for Fas was reduced (NR-O 1.89±1.56; O 4.68 ±1.72 2-(ΔCT) (p<0.05)). Our study suggests that abnormal patterns of renal adaptation are induced by juvenile obesity in NR offspring, with persistent changes in markers of oxidation. We have, therefore, shown, for the first time in this model of fetal programming, that increased systemic and renal oxidative stress alters the gene regulation of angiogenic and pro-apoptotic genes such as HIF-1α and Fas. These differential adaptations may delay the onset of glomerulosclerosis2 without necessarily improving vascular function.
Where applicable, experiments conform with Society ethical requirements