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

Abstract

Obesity is an independent risk factor for developing chronic kidney disease. Toll-like receptor 4 (TLR4), interleukin (IL)-18, and uncoupling protein 2 (UCP2) are important components of the innate immune system mediating inflammatory renal damage. Early to midgestation maternal nutrient restriction appears to protect the kidney from the deleterious effects of early onset obesity, although the mechanisms remain unclear. We examined the combined effects of gestational maternal nutrient restriction during early fetal kidney development and early onset obesity on the renal innate immune response in offspring. Pregnant sheep were randomly assigned to a normal (control, 100%) or nutrient-restricted (NR, 50%) diet from days 30 to 80 gestation and 100% thereafter. Offspring were killed humanely at 7 days or, following rearing in an obesogenic environment, at 1 yr of age, and renal tissues were collected. IL-18 and TLR4 expression were strongly correlated irrespective of intervention. Seven-day NR offspring had significantly lower relative renal mass and IL-18 mRNA expression. At 1 yr of age, obesity resulted in increased mRNA abundance of TLR4, IL-18, and UCP2, coupled with tubular atrophy and greater immunohistological staining of glomerular IL-6 and medullary tumor necrosis factor (TNF)-α. NR obese offspring had a marked reduction of TLR4 abundance and renal IL-6 staining. In 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. 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.

Maternal Body Weight and Gestational Diabetes Differentially Influence Placental and Pregnancy Outcomes

“…This could occur through changes in the activity of AMPK, Akt, and mTOR, with the former sensing energy depletion ( 46 ) and the latter stimulated by raised energy supply ( 43 ). Mitochondria also regulate ROS production and oxidative stress by uncoupling energy supply, with both AMPK and mTOR modulating oxidative stress through changes in UCP2 ( 47 ) and nuclear factor κB action ( 26 , 48 ), thereby promoting proinflammatory and pro-oxidative pathways within trophoblast cells. In contrast, mitochondrial replication is dependent on SIRT1 activity that also determines cell survival and senescence by inhibiting mTOR activity ( 49 ).Our findings are, therefore, indicative of a protective or physiological adaptation by the placenta against oxidative stress ( 49 , 50 ) with raised maternal BMI.…”

Nutrition, Epigenetics, and Metabolic Syndrome

“…Additionally, maternal nutrient restriction results in increased myocardial lipid and altered gene expression in offspring at 1 year of age (28). Moreover, in sheep, maternal nutrient restriction impairs renal function, increases the development of glomerulosclerosis, and enhances apoptosis in kidneys, while altering the expression of proteins involved in regulating inflammatory processes (155,192). In both pigs and sheep, maternal undernutrition also results in decreased skeletal muscle fiber number, increased deposition of adipose tissue, and increased connective tissue content (15,58).…”

Early life environment and developmental immunotoxicity in inflammatory dysfunction and disease

“…Early life microbial exposures facilitate the maturation of dendritic cells (DCs) (Hoeman, Dhakal, and Zaghouani 2010; Troy and Kasper 2010) and expand the repertoire of immune functions to include Th1, Th17, and other immune response patterns. Prenatal and/or early postnatal exposure to toxicants (e.g., alcohol, heavy metals, tobacco smoke), certain infectious agents (e.g., gram-negative bacteria), and dietary factors (e.g., prenatal overnutrition, postnatal formula feeding) can alter the normal trajectory of innate immune maturation contributing to tissue pathology rather than adequate host resistance and tissue homeostasis (Auten et al 2009; Beloosesky et al 2010; Bry, Hogmalm, and Backstrom 2010; Caicedo et al 2008; Calderon-Garciduenas et al 2009; Ding et al 2010; Fry et al 2007; Sharkey et al 2009; Tomat, Costa Mde, and Arranz 2011). These alterations in immune function have the potential to change the trajectory of subsequent pathogen-stimulated innate immune responses throughout life (Perrone et al 2010; Strunk et al 2011).…”