(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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066068-02
Application #
6527681
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Barouch, Winifred
Project Start
2001-09-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$251,000
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Kopp, Ulla C (2015) Role of renal sensory nerves in physiological and pathophysiological conditions. Am J Physiol Regul Integr Comp Physiol 308:R79-95
Mulder, Jan; Hokfelt, Tomas; Knuepfer, Mark M et al. (2013) Renal sensory and sympathetic nerves reinnervate the kidney in a similar time-dependent fashion after renal denervation in rats. Am J Physiol Regul Integr Comp Physiol 304:R675-82
Kopp, Ulla C; Cicha, Michael Z; Smith, Lori A (2011) Impaired interaction between efferent and afferent renal nerve activity in SHR involves increased activation of alpha2-adrenoceptors. Hypertension 57:640-7
Kopp, Ulla C; Cicha, Michael Z; Smith, Lori A et al. (2011) Dietary sodium modulates the interaction between efferent and afferent renal nerve activity by altering activation of ýý2-adrenoceptors on renal sensory nerves. Am J Physiol Regul Integr Comp Physiol 300:R298-310
Kopp, Ulla C (2011) Endothelin in the control of renal sympathetic nerve activity. Contrib Nephrol 172:107-19
Grisk, Olaf; Packebusch, Martin; Steinbach, Antje C et al. (2010) Endothelin-1-induced activation of rat renal pelvic contractions depends on cyclooxygenase-1 and Rho kinase. Am J Physiol Regul Integr Comp Physiol 299:R1602-9
Kopp, Ulla C; Cicha, Michael Z; Jones, Susan Y (2010) Activation of endothelin A receptors contributes to impaired responsiveness of renal mechanosensory nerves in congestive heart failure. Can J Physiol Pharmacol 88:622-9
Kopp, Ulla C; Grisk, Olaf; Cicha, Michael Z et al. (2009) Dietary sodium modulates the interaction between efferent renal sympathetic nerve activity and afferent renal nerve activity: role of endothelin. Am J Physiol Regul Integr Comp Physiol 297:R337-51
Kopp, Ulla C; Jones, Susan Y; DiBona, Gerald F (2008) Afferent renal denervation impairs baroreflex control of efferent renal sympathetic nerve activity. Am J Physiol Regul Integr Comp Physiol 295:R1882-90
Kopp, Ulla C; Cicha, Michael Z; Yorek, Mark A (2008) Impaired responsiveness of renal sensory nerves in streptozotocin-treated rats and obese Zucker diabetic fatty rats: role of angiotensin. Am J Physiol Regul Integr Comp Physiol 294:R858-66

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