Periods of decreased nutrient availability represent the most common life-threatening stressors in nature. The mechanisms involved in defense against nutritional deficits are fundamental to survival and therefore highly redundant. One strategy relies on hypo-metabolism to facilitate survival in the face of decreased nutrient availability. In the United States at least 50 million Americans live In households experiencing food insecurity and hunger, exposing millions of women and children to decreased nutrient availability. Deficits in kidney development have been a central theme in studies demonstrating how decreased maternal nutrition impacts fetal development and postnatal cardio-renal function. Despite this history, the factors that mechanistically link reduced fetal nutrient availability and intrauterine growth restriction (IUGR) to poor renal development, i.e. renal genomic, epigenomic and proteomic responses to decreased nutrient availability that underlie renal dysfunction in fetal primates are essentially unknown. Fundamental to Project 3 is our central hypothesis that limited fetal nutrient availability associated with IUGR induces biological strategies acting to preserve development and promote survival in the face of decreased nutrition; in other words, the IUGR fetal environment represents a hypo-metabolic state that leads to deficits in kidney development. We will test this hypothesis by studying maternal nutrient restriction (MNR; 30% reduction in control [CTR] diet) and intervention through maternal dietary leucine supplementation (INT) in pregnant baboons.
Four specific aims within P01 themes 2 (nutrient sensing), 3 (cell signalling) and 4 (function and epigenetics) examine the impact of MNR and INT on proximal tubule epithelial (PTE) cell nutrient sensing pathways (SAl), AMPK and mTOR signalling in PTE cell proliferation (SA2), epigenetic regulation of PTE cell growth (SA3), and PTE cell sodium transport function (SA4). Our approach utilizes Western blot, primary/ transformed cell culture, RNA Seq, miRNA Seq, proteomics (dimethylation/SILAC) and targeted promoter methylation. The significance lies in (1) studying maternal under nutrition, a serious public health problem, (2) exploring molecular mechanisms of non-human primate kidney development, and (3) improving understanding of the causes underiying complications of IUGR. Innovation lies in the multifaceted use of the non-human primate in integrating physiology, cell biology, proteomics, genomics, epigenomics, molecular biology and in silico methods to understand renal development and renal phenotype, creating the potential to devise therapeutic interventions to prevent and/or recuperate the impact of IUGR on kidney development and function.

Public Health Relevance

Reduced fetal nutrient availability results in suboptimal fetal growth and development that increases the risk of lifelong ill health including predisposition to diabetes and cardiovascular disease. This P01 integrates decreased maternal nutrient availability with placental function, fetal nutrient availability and fetal brain and fetal kidney development. In Project III we set out to study and identify key mechanisms in maternal x fetal nutrient environment interaction that will influence fetal kidney cell proliferation and proximal tubule function.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZHD1)
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University of Wyoming
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Kuo, Anderson H; Li, Cun; Huber, Hillary F et al. (2018) Ageing changes in biventricular cardiac function in male and female baboons (Papio spp.). J Physiol 596:5083-5098
Spradling-Reeves, Kimberly D; Glenn, Jeremy P; Lange, Kenneth J et al. (2018) The non-human primate kidney transcriptome in fetal development. J Med Primatol 47:157-171
Huber, Hillary F; Li, Cun; Nathanielsz, Peter W (2018) 2D:4D digit ratio is not a biomarker of developmental programming in baboons (Papio hamadryas species). J Med Primatol 47:78-80
Kuo, A H; Li, J; Li, C et al. (2018) Poor perinatal growth impairs baboon aortic windkessel function. J Dev Orig Health Dis 9:137-142
Kuo, Anderson H; Li, Cun; Mattern, Vicki et al. (2018) Sex-dimorphic acceleration of pericardial, subcutaneous, and plasma lipid increase in offspring of poorly nourished baboons. Int J Obes (Lond) 42:1092-1096
Light, Lydia E O; Bartlett, Thad Q; Poyas, Annica et al. (2018) Maternal activity, anxiety, and protectiveness during moderate nutrient restriction in captive baboons (Papio sp.). J Med Primatol :
Kuo, A H; Li, J; Li, C et al. (2017) Prenatal steroid administration leads to adult pericardial and hepatic steatosis in male baboons. Int J Obes (Lond) 41:1299-1302
Proffitt, J Michael; Glenn, Jeremy; Cesnik, Anthony J et al. (2017) Proteomics in non-human primates: utilizing RNA-Seq data to improve protein identification by mass spectrometry in vervet monkeys. BMC Genomics 18:877
Muralimanoharan, Sribalasubashini; Li, Cun; Nakayasu, Ernesto S et al. (2017) Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction. J Mol Cell Cardiol 108:181-193
Li, Cun; Jenkins, Susan; Mattern, Vicki et al. (2017) Effect of moderate, 30 percent global maternal nutrient reduction on fetal and postnatal baboon phenotype. J Med Primatol 46:293-303

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