Growth Regulation and Nutrient Sensing in the Fetal Baboon Kidney

点击翻译按钮获取中文摘要

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.