The current proposal will determine the role of P2 receptors in the impaired autoregulatory behavior exhibited by afferent arterioles from salt-sensitive hypertensive animals. Emphasis will focus on the responsiveness of the microvasculature to P2 receptor stimulation by ATP. Previous work from our laboratory has implicated ATP as the messenger molecule released from salt-sensing, macula densa cells to effect autoregulatory adjustments in preglomerular resistance. ATP is also considered to be essential element in the renal response to increased salt. Preliminary data indicate that autoregulatory capability and responsiveness to P2 receptor activation by ATP is attenuated in afferent arterioles in kidneys from angiotensin II-infused hypertensive rats. These observations support the central hypothesis that P2 receptors mediate autoregulatory adjustments in afferent arteriolar diameter and that P2 receptor activation is impaired in hypertension by the actions of locally generated cytokines. Accordingly, experiments will focus on the regional responsiveness of afferent arterioles from hypertensive and normotensive rats, to P2 receptor stimulation and will assess the impact of specific renal cytokines on these responses.
Specific Aim #1 will test the hypothesis that decreased P2 receptor activation mediates impairment of autoregulatory responses in kidneys from salt-sensitive hypertensive animals..
Specific Aim #2 will test the hypothesis that locally generated cytokines impair afferent arteriolar responsiveness P2 receptor activation. These studies will focus on the microvascular responsiveness to P2 receptor activation and the calcium influx pathways utilized by them in the myogenic and TGF-dependent regions of the afferent arteriole.
Specific Aim #3 will test the hypothesis that influx-dependent Ca 2+ signaling mechanisms are responsible for impaired autoregulatory responsiveness in animals developing salt-sensitive hypertension. We will use freshly isolated preglomerular smooth muscle cells from kidneys of normotensive and hypertensive rats fed normal and high salt diets. Calcium signaling pathways invoked by P2 receptor activation will be examined using fura-2. We will assess the impact of chronic infusions of IL-6 or TGF-beta on the calcium influx pathways invoked by P2 receptor stimulation.
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