PURINERGIC REGULATION OF THE RENAL MICROVASCULATURE

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The dual contribution of myogenic and tubuloglomerular feedback (TGF) influences to autoregulation is generally accepted; however, the chemical messenger(s), receptors and signaling pathways involved remain unknown. In the last 5 years, we have provided compelling evidence that P2 purinoceptor activation can significantly impact renal microvascular function. Based on the observation that P2 receptor activation by ATP participates importantly in autoregulatory behavior by selectively modulating preglomerular resistance, we hypothesize that ATP-mediated P2 receptor activation provides the "chemical signal" for transducing hemodynamic stimuli into autoregulatory responses. In the next period of funding, we wish to build on these exciting observations by determining the mechanisms by which ATP influences preglomerular microvascular function, and by exploring the involvement of P2 receptors in the myogenic and TGF-mediated components of renal autoregulatory behavior. We will directly determine the involvement of P2 receptors in myogenic and TGF-mediated autoregulatory responses using the juxtamedullary nephron preparation. These studies will include normotensive animals which exhibit normal autoregulatory behavior and hypertensive animals with impaired autoregulatory capability. We will also explore the paracrine influence of locally released endothelial factors on the preglomerular responses to P2 receptor activation. These studies will address specific renal hemodynamic issues relevant to normal kidneys and the renal damage associated with the renal microvascular dysfunction observed in hypertensive states. We will extend the functional responses obtained with intact afferent arterioles to the cellular level by examining the intracellular signaling pathways and membrane currents invoked by P2 receptor activation in freshly isolated, preglomerular microvascular smooth muscle cells. Collectively, the results of these studies will provide a comprehensive understanding of the contribution of renal microvascular P2 receptors to myogenic and TGF-mediated autoregulatory responses by afferent arterioles; and will reveal the intracellular signaling cascades invoked by P2 receptors to regulate afferent arteriolar function in normotensive and hypertensive states.