Browsing by Subject "Angiotensin"

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    The role of renin in the adipose tissue renin-angiotensin system.
    (2009-07) Fowler, Jason Dean
    The renin angiotensin system (RAS) has been implicated in a variety of adipose tissue functions including tissue growth, differentiation, metabolism, and inflammation. While expression of all components necessary for a locally derived adipose tissue RAS have been demonstrated within adipose tissue, independence of local adipose RAS component concentrations from corresponding plasma RAS fluctuations has not been addressed. To analyze this, we varied in vivo rat plasma concentrations of two RAS components, renin and angiotensinogen (AGT), to determine the influence of their plasma concentrations on adipose and cardiac tissue levels in both perfused (plasma removed) and nonperfused samples. Variation of plasma RAS components was accomplished by 4 treatment groups: Normal, DOCA-salt, Bilateral nephrectomy, and Losartan. Adipose and cardiac tissue AGT concentrations correlated positively with plasma values. Perfusion of adipose tissue decreased AGT concentrations by 11.1% indicating that adipose tissue AGT was in equilibrium with plasma. Cardiac tissue renin levels positively correlated with plasma renin concentration for all treatments. In contrast, adipose tissue renin levels did not correlate with plasma renin, with the exception of extremely high plasma renin concentrations achieved in the Losartan treated group. These results suggest that adipose tissue may control its own local renin concentration independently of plasma renin as a potential mechanism for maintaining a functional local adipose RAS. Whereas adipose tissue possesses a local renin-angiotensin system, the synthesis and regulated release of renin has not been addressed. To that end we utilized differentiating 3T3-L1 cells and analyzed renin expression and secretion. Renin mRNA expression and protein enzymatic activity were not detectable in preadipocytes. However, upon differentiation, renin mRNA and both intracellular and extracellular renin activity were up regulated. In differentiated adipocytes, forskolin treatment resulted in a 28-fold increase in renin mRNA while TNF alpha treatment decreased renin mRNA 4-fold. IL-6, insulin, and angiotensin II (Ang II) were without effect. In contrast, forskolin and TNF alpha each increased renin protein secretion by 12- and 7-fold, respectively. Although both forskolin and TNFalpha induce lipolysis in adipocytes, fatty acids, prostaglandin E2 or lipopolysaccharide had no effect on renin mRNA or secretion. To evaluate mechanism(s) by which forskolin and/or TNF alpha are able to regulate renin secretion, a general lipase inhibitor (E600) and PKA inhibitor (H89) were used. Both inhibitors attenuated forskolin induced renin release while having no effect on TNF alpha regulated secretion. In contrast, E600 potentiated forskolin-stimulated renin mRNA levels while H89 had no effect. Neither inhibitor had any influence on TNFalpha regulation of renin mRNA. Relative to lean controls, renin expression was reduced 78% in the epididymal adipose tissue of obese male C57Bl/6J mice, consistent with TNF alpha-mediated down regulation of renin mRNA in the culture system. In conclusion, the expression and secretion of renin are regulated under a complex series of hormonal and metabolic determinants in mature 3T3-L1 adipocytes.
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    Role of the median preoptic nucleus in chronic blood pressure regulation by angiotensin II
    (2008-12) Ployngam, Trasida
    The median preoptic nucleus (MnPO) receives dense reciprocal inputs from both the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), the circumventricular organs known to be important as central neural sensors of circulating angiotensin II (ANG II). This thesis proposes to establish the role of the MnPO in chronic regulation of blood pressure based on the central hypothesis that the MnPO is a crucial component of the central sympathoexcitatory circuitry necessary for chronic blood pressure control following ANG II activation of the SFO and OVLT. Throughout the studies, cardiovascular responses to either pharmacological or physiological changes of circulating ANG II activity were compared between MnPO lesioned rats and sham lesioned controls. The first specific aim was designed to test the hypothesis that the intact MnPO is necessary for the full hypertensive response to chronic intravenous ANG II administration. In this specific aim, rats with electrolytic lesion of the MnPO displayed significantly attenuated hypertensive responses by day 7 through day 10 of ANG II infusion compared to sham lesioned rats. Therefore, we concluded that the MnPO is a crucial component of the central neuronal circuitry mediating chronic ANG II-induced hypertension. Sub-aim 1A was designed to determine the specific role of the MnPO neurons versus fibers of passage in the attenuated hypertensive responses to ANG II observed in the MnPO lesioned rats. In line with the findings of specific aim 1, rats with ibotenic acid lesion of the MnPO demonstrated attenuated responses to the hypertensive effect of chronic ANG II administration. However, the attenuated responses were less extensive relative to those seen in the electrolytic lesioned rats. Therefore, it was concluded that neuronal cell bodies in the MnPO are necessary for the full hypertensive response to chronic ANG II administration; however, damage of the fibers of passage partly contributes to the attenuated hypertensive responses observed in the electrolytic lesioned rats. The second specific aim was to determine the role of the MnPO in mediating the chronic hypotensive effect of the AT1 receptor antagonist, losartan. In this specific aim, rats with ibotenic acid lesion of the MnPO showed exaggerated hypotensive responses to chronic losartan administration. These findings were accompanied with a greater decline in total peripheral resistance in the MnPO lesioned rats. Therefore, we concluded that MnPO neurons do not mediate the chronic hypotensive effect of losartan and that the MnPO is not necessary for basal blood pressure control by endogenous ANG II. However, the findings suggested that the MnPO neurons likely participate in baroreflex mechanisms buffering against losartan-induced hypotension. The last specific aim was to establish the role of the MnPO in normal blood pressure control during chronic high dietary salt intake. Although plasma sodium concentration and osmolality were raised significantly in rats with electrolytic lesion of the MnPO during high salt intake, their mean arterial pressure and heart rate were comparable with those of sham lesioned rats throughout the study. Therefore, we concluded that the MnPO is not necessary to maintain normal blood pressure during high dietary salt intake. However, MnPO lesioned rats displayed less renal sodium retention during high salt intake compared to sham lesioned rats suggesting the role of the MnPO in the central neurohumoral control of sympathetic outflow, in particular, renal sympathetic activity, during chronic high salt intake. In conclusion, overall, the findings in this dissertation provide important insights into the role of the MnPO in the chronic hypertension induced by ANG II. Furthermore, they provide additional evidence of the integrative role of the MnPO in chronic normal blood pressure control by circulating ANG II, plasma osmolality, and the baroreflex.