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The renal microvasculature is highly sensitive to hyperglycemia.
The global prevalence of diabetes in pregnancy is increasing, and maternal hyperglycemia is a significant risk factor for the development of genitourinary defects and renal malformations. In addition, there is evidence from animal models that prenatal exposure to hyperglycemia can lead to reduced nephron endowment, which itself increases the likelihood of chronic kidney disease in childhood and beyond. Taken together, maternal diabetes represents an important contributor to the leading cause of chronic kidney disease in children. Postnatally, the pathogenesis of diabetic nephropathy has been linked to damage to the microvasculature of the kidney, and aberrant miRNA expression. However, the molecular mechanisms that underlie the effect of hyperglycemia on kidney development in utero are unknown. Our laboratories (Ho and Sims-Lucas) have significant expertise in renal development, specifically as it pertains to formation of the renal microvasculature and miRNA function. We have extended the expertise of our research team by including Dr. Jon Piganelli, a prominent immunologist and diabetes researcher. We have preliminary data demonstrating that human fetal kidney endothelial cells undergo oxidative stress when exposed to hyperglycemia. We hypothesize that maternal hyperglycemia results in impaired nephrogenesis as a result of altered miRNA function and aberrant differentiation of the kidney vasculature. Thus, we propose the following: Aim 1: To characterize the RNA and small RNA transcriptome of human fetal kidneys and isolated fetal endothelial cells exposed to hyperglycemia. Aim 2: To validate the mis-regulation of mRNA and miRNA expression in response to hyperglycemia in vitro and in the streptozotocin-induced mouse model of diabetes.

Understanding how exposure to maternal diabetes impacts kidney development.
The number of pregnant women with diabetes has increased markedly worldwide, with one estimate suggesting that as many as 1 in 14 women may be affected by diabetes during pregnancy (including women with Type 1 diabetes, Type 2 diabetes and gestational diabetes (diabetes associated with pregnancy)). Children of women with diabetes during pregnancy are more likely to have congenital anomalies of the kidneys, which are amongst the most common causes of kidney disease in children. Indeed, it has been shown that there is an increased incidence of chronic kidney disease in individuals who are exposed to maternal diabetes in utero. Our laboratory is interested in studying why children who are born to mothers with diabetes are more likely to have kidney disease. To do this, we have developed a mouse model of maternal diabetes. Mice exposed to maternal diabetes have about 20% less nephrons than mice that are born from mothers without diabetes. In this proposal, we will use this mouse model to study: (1) why the kidneys of animals exposed to diabetes before birth have fewer nephrons; and (2) whether these mice are more prone to kidney problems with age.

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