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Maternal nutrient restriction during early fetal kidney development attenuates the renal innate inflammatory response in obese juvenile offspring

Presented at the Neonatal Society 2009 Summer Meeting (programme).

Sharkey D1, Gardner DS2, Symonds ME1, Budge H1

1 Early Life Nutrition Research Unit, School of Clinical Sciences, University of Nottingham, Nottingham, UK
2 School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK

Introduction: The rising worldwide incidence of end-stage renal disease (ESRD) has significant health and economic implications. Obesity, a component of the metabolic syndrome, is an independent risk factor for the development of ESRD and is worrying in the face of increasing childhood obesity. The innate immune system plays an important part in the inflammatory dysregulation observed in the metabolic syndrome. IL-18 and toll-like receptor 4 (TLR4) are important innate inflammatory genes in acute renal injury and diabetic nephropathy. We have previously shown, in an ovine model, that early-to-mid maternal nutrient restriction appears to protect the kidney from the deleterious effects of juvenile obesity although the mechanisms remain unclear (1). The extent to which alterations occur in these key genes following gestational nutrient restriction and early-onset obesity is unknown. We examined the combined effects of maternal nutrient restriction during pregnancy and early-onset obesity on the renal innate immune response in offspring.

Methods: Eighteen twin-bearing pregnant sheep were randomly assigned to a normal (C, 7 MJ/day, n=8) or nutrient restricted (NR) diet (NR, 3.5 MJ/day, n=10) from days 30 to 80 gestation (term=147 days). The timing of nutrient restriction coincides with the early development of the metanephros (final kidney). One twin was humanely euthanased at 7 days of age with the remaining twin reared, following weaning, in an obesogenic environment. At 1 year of age, they were humanely euthanased and renal tissues sampled. The mRNA abundance of IL-18 and TLR4 in renal tissues was measured by real-time PCR. IL-6 and TNF were quantified and distribution explored using immunohistochemistry. Home Office and Animal Ethics Committee approval was obtained. Data are expressed as mean sem with mRNA expressed as fold change (a.u.).

Results: At 7 days, NR offspring had a lower relative kidney mass (C 6.90.4g/kg vs NR 5.80.2g/kg, P<0.01) and downregulation of IL-18 (C 1.00.2, NR 0.40.1, P<0.05) but not TLR4 (C 1.00.3, NR 0.40.1, P=0.11) gene expression. In lean animals, a strong positive correlation existed between renal IL-18 and TLR4 (r2=0.87, P<0.0001). In obese juvenile offspring, IL-18 was not different between groups (C 3.30.7, NR 2.30.4). However, glomerular IL-6 staining was significantly lower in the NR offspring (C 997411, NR 20695 a.u., P<0.05) with no significant differences noted in medullary TNF (C 2.20.7x105, NR 0.70.5x105 a.u.).

Conclusion: Maternal nutrient restriction during early fetal kidney development attenuates the effects of early-onset obesity-related nephropathy, in part, through the downregulation of the innate inflammatory response. IL-18 and TLR4 are important components of the inflammatory mechanisms leading to obesity-related renal damage and appear susceptible to in utero nutritional programming conferring an element of renal protection. A better understanding of maternal nutrition and the in utero nutritional environment may offer therapeutic strategies aimed at reducing the burden of later kidney disease.

Acknowledgements: This study was supported by the British Heart Foundation.

1. Sharkey et al, FASEB J 2009;23:1314-1324.

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