Extensive data in experimental animals indicate that fetal exposure to glucocorticoids (GC) is associated with long term effects, however, the mechanisms remain largely unknown. During the previous funding period we showed that a single course of betamethasone elevates arterial blood pressure in the adult offspring and is associated with a 25% decrease in nephron number, but without an impairment of renal function, and alterations in vascular reactivity compatible with a dysfunction of the endothelin system. In humans and in animals, antenatal GC exposure is associated with glucose tolerance abnormalities. In this competitive continuation we will test the hypothesis that .A derangement in the endothelin system plays a central causative role in the long-term cardiovascular and metabolic abnormalities present in adults exposed antenatally to glucocorticoids.. Specifically we hypothesize that in the adult offspring exposed antenatally to glucocorticoids: 1) The upregulation of the endothelin (ET) system plays a central role in the development of hypertension and glucose intolerance/insulin resistance;2) There is a synergistic interaction between antenatal glucocorticoid exposure and obesity that exaggerates the cardiovascular and metabolic effects of the ET system; 3) Following antenatal steroid exposure the development of insulin resistance establishes a positive feedback loop and enhances the contribution of the endothelin system to the increase in arterial blood pressure. We will test these hypotheses with the following specific aims:
Specific Aim 1 : To determine if the ET system contributes to the development of hypertension following antenatal glucocorticoid exposure.
Specific Aim 2 : To determine if diet-induced obesity exacerbates the cardiovascular and metabolic effects of the endothelin system in glucocorticoid exposed animals.
Specific Aim 3 : To determine the interactions of obesity/insulin resistance and the endothelin system on the cardiovascular and metabolic effects of antenatal glucocorticoid exposure. Given the increasing incidence of obesity and the mounting evidence for a developmental origin of cardiovascular disease, the studies proposed will determine the role of the ET-1 system and the interaction between antenatal glucocorticoid exposure and obesity.
In humans and in animals, antenatal glucocorticoid exposure is associated with elevations in blood pressure and glucose tolerance abnormalities. The proposed studies will determine if the endothelin system plays a critical role in the development of these abnormalities and if obesity in adulthood magnifies the alterations already present in those exposed prenatally to glucocorticoid. This information will aid in establishing new preventive interventions and therapeutic approaches in populations at risk for developing hypertension in adult life.
|Lee, J-H; Zhang, J; Massmann, G A et al. (2014) Antenatal betamethasone increases vascular reactivity to endothelin-1 by upregulation of CD38/cADPR signaling. J Dev Orig Health Dis 5:56-62|
|Lee, Jeong-Heon; Zhang, Jie; Flores, Lourdes et al. (2013) Antenatal betamethasone has a sex-dependent effect on the in vivo response to endothelin in adult sheep. Am J Physiol Regul Integr Comp Physiol 304:R581-7|
|Shaltout, Hossam A; Chappell, Mark C; Rose, James C et al. (2011) Exaggerated sympathetic mediated responses to behavioral or pharmacological challenges following antenatal betamethasone exposure. Am J Physiol Endocrinol Metab 300:E979-85|
|Zhang, Jie; Massmann, G Angela; Rose, James C et al. (2010) Differential effects of clinical doses of antenatal betamethasone on nephron endowment and glomerular filtration rate in adult sheep. Reprod Sci 17:186-95|
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|Contag, Stephen A; Bi, Jianli; Chappell, Mark C et al. (2010) Developmental effect of antenatal exposure to betamethasone on renal angiotensin II activity in the young adult sheep. Am J Physiol Renal Physiol 298:F847-56|
|Tang, Lijun; Carey, Luke C; Bi, Jianli et al. (2009) Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep. Am J Physiol Regul Integr Comp Physiol 296:R309-17|
|Shaltout, Hossam A; Westwood, Brian M; Averill, David B et al. (2007) Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II. Am J Physiol Renal Physiol 292:F82-91|
|Massmann, G Angela; Zhang, Jie; Rose, James C et al. (2006) Acute and long-term effects of clinical doses of antenatal glucocorticoids in the developing fetal sheep kidney. J Soc Gynecol Investig 13:174-80|
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