Chronic adult diseases, such as hypertension, diabetes or obesity, may develop as a consequence of early life stress (ELS). Adverse childhood events are highly correlated with enhanced cardiovascular response to a secondary stressor, a """"""""second hit"""""""". Maternal separation is an established model of chronic behavioral stress in rodents that involves separating pups from their mothers 3 hr/day from days 2-14 of life. Adult maternally separated (MS) rats show lower glomerular filtration rate under baseline conditions compared to control, un-separated littermates, with no difference in blood pressure. Interestingly, the phenylephrine-induced vasoconstriction in the kidney is attenuated but the drop in blood pressure elicited by ganglion blockade is greater in MS rats. These data suggest increased sympathetic activation in MS rats. In contrast, the acute pressor response to angiotensin II (AngII) is comparable between MS and control rats whereas MS rats show exaggerated chronic AngII-induced hypertension. Thus, our data suggest that ELS impairs the ability of the kidney to control blood pressure following a """"""""second hit"""""""". Taken together, we hypothesize that rats exposed to MS display increased renal sympathetic nerve activity (RSNA), which enhances vascular tone in the kidneys and impairs the physiological regulation of blood pressure. Given the fact that RSNA can increase AngII type 1 (AT1) receptor expression, we speculate that increased baseline RSNA in MS rats results in increased renal AngII system components, predisposing these rats to cardiovascular disease. In an original approach to model the growing epidemic of children with extremely poor dietary lifestyles, we exposed the rats to a high fat diet (HFD) as a secondary stressor. Our data show a fat-induced increase in blood pressure develops in rats exposed to ELS compared to control rats. Furthermore, we observed increased plasma leptin, corticosterone, aldosterone and renin activity in MS rats. These compelling data support the hypothesis that ELS impairs maintenance of blood pressure homeostasis in response to """"""""second hits"""""""" in adult life. The mentored phase will focus on the investigation of the RSNA and AT1-dependent mechanisms by which ELS exacerbates AngII-induced hypertension in adult rats, followed by the independent phase focused on the study of mechanisms by which ELS exacerbates blood pressure sensitivity to a HFD in adult rats. This novel proposal will investigate the following four aims: (1) to test the hypothesis that increased RSNA impairs renal capacity to control blood pressure in response to chronic AngII infusion in adult MS rats;(2) to test the hypothesis that exaggerated AT1 receptor activation increases renal vasoconstriction and reduces basal renal filtration capacity, enhancing AngII-induced hypertension in adult MS rats;(3) To test the hypothesis that MS increases sensitivity of blood pressure in response to a HFD through a renal mechanism;and (4) To test the hypothesis that HFD increases AngII in adipose tissue and induces AT1 dependent increase in blood pressure in MS rats.

Public Health Relevance

Adverse environment during early life is known to sensitize humans to stressors and risk factors for hypertension and cardiovascular disease later in life. Similarly, early life stressors sensitize rats in the adulthood, in part, by exacerbating the responses to AngII. Diseases derived from pediatrics issues such as prematurity and adverse childhood increase dramatically the annual public health cost. Therapeutic strategies during perinatal life will be guided by the elucidation of novel mechanisms by which ELS elicits an organ- programmed dysfunction, increasing the susceptibility to cardiovascular and renal disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Transition Award (R00)
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No Study Section (in-house review) (NSS)
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Maric-Bilkan, Christine
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University of Kentucky
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De Miguel, Carmen; Obi, Ijeoma E; Ho, Dao H et al. (2018) Early life stress induces immune priming in kidneys of adult male rats. Am J Physiol Renal Physiol 314:F343-F355
Loria, Analia S; Spradley, Frank T; Obi, Ijeoma E et al. (2018) Maternal Separation Enhances Anti-contractile Perivascular Adipose Tissue Function in Male Rats on a High Fat Diet. Am J Physiol Regul Integr Comp Physiol :
Murphy, Margaret O; Herald, Joseph B; Leachman, Jacqueline et al. (2018) A model of neglect during postnatal life heightens obesity-induced hypertension and is linked to a greater metabolic compromise in female mice. Int J Obes (Lond) 42:1354-1365
Fox, Brandon M; Becker, Bryan K; Loria, Analia S et al. (2018) Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium-Derived Endothelin-1. J Am Heart Assoc 7:
Murphy, M O; Cohn, D M; Loria, A S (2017) Developmental origins of cardiovascular disease: Impact of early life stress in humans and rodents. Neurosci Biobehav Rev 74:453-465
Loria, Analia S; Osborn, Jeffrey L (2017) Maternal separation diminishes ?-adrenergic receptor density and function in renal vasculature from male Wistar-Kyoto rats. Am J Physiol Renal Physiol 313:F47-F54
Murphy, Margaret O; Loria, Analia S (2017) Sex-specific effects of stress on metabolic and cardiovascular disease: are women at higher risk? Am J Physiol Regul Integr Comp Physiol 313:R1-R9
Murphy, Margaret O; Herald, Joseph B; Wills, Caleb T et al. (2017) Postnatal treatment with metyrapone attenuates the effects of diet-induced obesity in female rats exposed to early-life stress. Am J Physiol Endocrinol Metab 312:E98-E108
Loria, Analia S (2016) Can we fight chronic kidney disease by targeting endothelial HB-EGF? Am J Physiol Renal Physiol 311:F406-8
Loria, Analia S; Pollock, David M; Pollock, Jennifer S (2015) Angiotensin II is required to induce exaggerated salt sensitivity in Dahl rats exposed to maternal separation. Physiol Rep 3:

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