(Verbatim from the application): Increased renal pelvic pressure from acute ureteral obstruction or high urine flow rate stretches the renal pelvic wall and activates renal pelvic mechano sensitive neurons leading to increases in afferent renal nerve activity (ARNA) and urinary sodium excretion, a renorenal reflex. The renorenal reflexes are impaired in hypertension. Long-term Objectives: To study (1) the renorenal reflex-mediated control of water and Na+ excretion during changes in dietary Na+ in rats and mice lacking the genes encoding mediators involved in the activation of renal sensory neurons, (2) the interaction among cyclooxygenase-2 (COX-2), angiotensin and nitric oxide (NO) in the activation of rena] mechanosensory neurons and (3) the essential role of substance P (SP).
Specific Aim#1. Mechanisms involved in the increased responsiveness of renal mechanosensitive neurons during high Na+ diet: (a). Is the enhanced responsiveness of the renal mechano sensitive neurons during increased Na+ diet due to increased release/activation of bradykinin, COX-2, PGE2 and/or SP? (b). Does the renin-angiotensin system modulate the activation of renal mechanosensitive neurons? Specific Aim#2. Role of NO as an inhibitory neurotransmitter in the activation of renal mechanosensory neurons: (a). Does NO alter renal pelvic contractility and/or renal pelvic release of PGE2, SP and calcitonin gene-related peptide (CGRP)? (b). Does NO desensitize renal pelvic bradykinin B2 and/or SP receptors? Specific Aim#3. Characterization of renorenal reflexes in mutant mice lacking the gene encoding SP. (a). Is substance P essential foi activation of renal mechanosensitive neurons? (b). Are substance P receptors located on substance P containing neurons and/or sympathetic neurons in the renal pelvis? Renal mechanosensitive neurons will be stimulated b3 increasing renal pelvic pressure in anesthetized mice and rats and ARNA will be recorded. Release of SP, PGE2 anc CGRP will be measured from the renal pelvis by ELISA. Immunohistochemistry will be used to localize the various mediators involved. Identifying the mechanisms involved in the activation of the renal sensory neurons during changes in dietary Na+ in rats and mice may further our understanding of the renal mechanisms contributing to hypertension.
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