Low Birth Weight, Blood Pressure, and Kidney Disease

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Project Summary Low birth weight (LBW) is an important risk factor for hypertension, cardiovascular and kidney disease; however, the mechanisms by which an adverse fetal environment programs risk for adult disease are poorly understood. Because this risk factor is determined at the beginning of a person’s lifespan, a better understanding of developmental programming can provide insight that improves early disease prevention and intervention to drastically reduce the burden of disease in later adulthood. Novel findings in this area also have great potential to reduce health disparities, as African-Americans are disproportionately affected by LBW and other conditions linked to this risk factor including hypertension and chronic kidney disease. Placental insufficiency is the most common cause of LBW in the Western world, and the reduced uterine perfusion pressure (RUPP) animal model of preeclampsia mimics the same health effects seen in human offspring, including the sex differences in how programming influences cardio-renal disease. Evidence suggests that renal inflammation plays a mediatorial role in the link between hypertension and kidney damage. The objective of this project is to study the effects of chronic elevations in blood pressure on renal health in intrauterine growth restricted (IUGR) offspring, and to elucidate the mechanisms by which changes during development lead to increased renal risk in later life in a sex-specific manner. This will be done by inducing a secondary insult of reduced renal mass by uni-nephrectomy in 18 month old IUGR offspring, and comparing physiological indicators of renal function as well as molecular and histological markers of tissue injury between control and IUGR males and females. Blood pressure-lowering and anti-inflammatory medications will also be used to determine whether early intervention can prevent this renal damage in response to an insult. Aim 1 will test the hypothesis that intrauterine growth restriction programs a long-term increase in blood pressure in males that initiates a progressive accelerated age-related decline in renal function leading to an enhanced susceptibility to renal injury in growth-restricted rats. Aim 2 will test the hypothesis that intrauterine growth restriction programs enhanced up-regulation of renal TNF-α and TGF-β1 in response to a secondary renal insult that contributes to enhanced susceptibility to renal injury in growth-restricted rats.