Autoregulatory control is an intrinsic property of the preglomerular microvasculature that involves myogenic control of lumenal diameter combined with the tubuloglomerular feedback(TGF) mechanism for enhanced capability. Macula densa cells of the distal tubule serve as "sensors" monitoring distal tubular fluid flow and/or composition. Exactly, how the macula densa communicates the need to adjust afferent arteriolar resistance and the identity of the "messenger molecule" remains poorly understood. Previous studies from our laboratory have led to our central hypothesis that ATP mediates TGF-dependent renal vasoconstriction via P2X1 and P2Y2 receptor activation, and thereby plays an important role in preventing hypertensive glomerular injury. Bell and coworkers recently reported that macula densa cells indeed release ATP in response to stimuli that evoke TGF signals. We have shown that inactivation of P2X1 receptor signaling, simultaneously interrupts autoregulatory vasoconstriction. Both autoregulatory capability and P2X1 receptor activation are impaired in kidneys from hypertensive animals. Therefore, P2X1 receptor activation is a likely target for investigating the mechanisms responsible for the hypertension-induced decline in autoregulatory capability. Adenosine is also postulated as the signaling molecule mediating TGF responses, and recent work, performed using A 1 receptor knockout mice, has renewed interest in this idea. The hypothesis dictates that TGF-mediated, afferent arteriolar vasoconstriction involves activation of A1 receptors. The current proposal will take a comprehensive look at these two competing hypotheses and will resolve several important questions that exist regarding identification of the signaling mechanism responsible for TGF. Experiments will be performed using unique P2X1 and A1 receptor knockout mice and will directly examine the mechanisms of microvascular autoregulatory control. Studies are divided into three specific aims. Specific aim 1 will test the hypothesis that TGF-mediated vasoconstriction is impaired in mice lacking the P2X1 receptor. Specific aim 2 will test the hypothesis that calcium influx and activation of the Rho-kinase pathway contribute to the sustained autoregulatory vasoconstriction evoked by P2X1 and P2Y2 receptor activation. Specific aim 3 will test the hypothesis that P2X1 receptor ablation will exacerbate hypertension related renal injury in response to angiotensin II-dependent, salt-sensitive hypertension. The results of these studies will provide new information on the mechanisms of P2X1 receptor mediated regulation of renal microvascular function, and the relationship between P2X 1 receptor activation and renal damage associated with impairment of preglomerular autoregulatory performance.
NIH ExPorter
NIH ExPorter