Maternal under-nutrition (MUN) results in intrauterine growth restriction (IUGR) of the fetus, which markedly increases the lifelong adult risk of heart disease, obesity, type II diabetes, and other components of the metabolic syndrome. IUGR-related programming of the kidney gives rise to adult nephropenia (reduced glomerular number) and elevation in adult arterial blood pressure. Mechanisms for and strategies for prevention of this form of programmed renal injury are poorly understood. The investigators recently identified significant down-regulation of the Glial derived neurotrophic factor (GDNF) and Notch signaling pathways during MUN nephrogenesis. They hypothesize that programmed down-regulation of these signaling pathways leads to a reduction of iterative ureteric bud branching, MAPK/ERK signaling, and renin-angiotensin system gene expression, which ultimately results in reduced glomerular number, abnormal glomerular maturation, and adult hypertension. A proposed early event in this process, WT1 upregulation, is modulated by epigenetic MUN programming. In the investigators'model, maternal rat dams are fed a 50% reduced diet from day 10 of gestation to postnatal day 8. They will identify the key time point during fetal kidney development when ureteric branching and glomerulogenesis are susceptible to IUGR. They will examine the programmed down-regulation of the GDNF and Notch signaling pathways, MAPK/ERK activation, and intra-renal RAS gene expression by real time RT-PCR and Western blotting, as well as regional kidney and glomerular expression by immunohistochemistry and in situ hybridization. Epigenetic programming of WT1 will be characterized. To confirm the putative signaling mechanisms, the will induce over-expression of the GDNF and Notch signaling pathways using recombinant protein, siRNA, and viral gene expression vectors in ex vivo MFR kidney explants to replicate/prevent the effects of IUGR on ureteric branching, glomerular formation, and signal transduction pathways. These findings will provide a mechanistic analysis of the impact of MUN on programmed nephrogenesis, and provide a translational framework for treating fetal programming in humans.
Low birth weight newborns are born with kidneys deficient in nephron number as well as permanent changes in gene expression due to the maladaptive fetal environment. These studies are designed to provide insights into the molecular changes in kidney development that occur due to this form of fetal programming. The investigators'long term goal is to identify key developmental points in fetal kidney growth and to reverse the condition through therapeutic treatments
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