Our studies in the previous funding period showed that both aging and hypertension are associated with a functional deficiency of Ang-(1-7) within the nucleus of the solitary tract (nTS) accompanying the increase in resting mean arterial pressure (MAP) and impairment of baroreceptor reflex sensitivity (BRS) for control of heart rate. Moreover, we provided evidence that long-term alterations of the brain renin-angiotensin system (RAS) impact not only MAP and BRS, but also metabolic function (leptin, insulin and body weight) over the lifespan in rats. The effects of aging and hypertension may be related to differential regulation of specific cellular sources (neurons vs. glia) of Ang II and Ang-(1-7). Preliminary studies suggest that differences in precursor pathways may also exist, since a highly selective antibody to Ang-(1-12) [Anti-Ang-(1-12) IgG] given intracerebroventricularly lowers MAP in (mRen2)27 transgenic rats.
Aim 1 will determine if long-term selective blockade of brain Ang II vs Ang-(1-7), including blockade of potentially different cellular sources or precursors, has divergent actions on MAP, BRS and metabolic function in hypertension and aging. Ang II, insulin and leptin share signaling pathways including phosphoinositol 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK). Protein tyrosine phosphatase (PTP) 1b and dual specificity phosphatases (DUSP-1) are known negative modulators of the kinase pathways, decreasing functional responses to Ang II, leptin and insulin in a variety of settings. We discovered that inhibitors of PI3K lower MAP and improve BRS in (mRen2)27 hypertensive rats, but not Sprague-Dawley (SD) rats. Preliminary data show that inhibition of PTP1 b impairs BRS in SD rats, suggesting that in healthy animals, the PTP1 b provides a positive influence on reflex function. Gene transfer of Ang-(1-7) via fusion-protein-containing plasmid in (mRen2)27 rats with high Ang II and low Ang-(1-7) in the medulla, increases expression of PTP1b and DUSP-1 in dorsomedial medulla, associated with a reduction in MAP and an improvement in BRS. However, PTP1 b is reported to participate in leptin resistance in brain hypothalamic nuclei;therefore, increases in the activity of this phosphatase by Ang-(1-7) might be expected to impair metabolic function.
Aim 2 will now investigate whether (a) MAPK and PI3K pathways and their respective negative modulators, DUSP-1 and PTP1b, are differentially regulated with long-term alterations in the brain or peripheral RAS, and (b) whether the differential regulation contributes to changes in MAP, BRS and metabolic function (effects of insulin and leptin on MAP and BRS) within the nTS.
Aim 3 will evaluate the long-term consequences of increases in Ang II or Ang-(1-7), or both, in the circulation on the regulation in brain of components of the RAS and the specific signaling pathways of interest. We propose that Ang-(1-7) counteracts the negative effects of Ang II, insulin and leptin on MAP and BRS via increasing the levels of DUSP1 and PTP1b in the nTS. However, Ang-(1-7) mediated upregulation of the PTP1b signaling pathway may contribute to resistance to leptin in hypothalamic pathways involved in body weight and energy control.
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