Hypertension (HTN) is linked to increased sympathetic nervous system activity (SNA) and increased activity of renal efferent nerves is thought to be important. However, the kidneys are also innervated by renal afferent nerves, which project to central nervous system circuits that modulate SNA to various peripheral targets. As such, increased afferent renal nerve activity (ARNA) is also postulated to contribute to increased SNA and the pathogenesis of HTN. Renal denervation (RDNx) for treatment of HTN in humans is now possible. However, the mechanisms by which RDNx lowers AP remain unknown. An emerging new theory of HTN may provide new insights. It is hypothesized that HTN is caused, in part, by a close relationship between renal nerves, renal inflammation, and HTN. These findings suggest that the antihypertensive response to RDNx is not due to disruption of neural control of renal function per se, but rather, blockade of the interaction of immune cells with efferent and afferent renal nerves. These findings led to the Central Hypothesis of this proposal: DOCA-salt HTN is caused, in part, by the action of proinflammatory cytokines on afferent renal nerves resulting in neurogenically mediated HTN.
Four Specific Aims will rigorously test this Central Hypothesis.
Specific Aim 1 : Investigate the neurophysiological mechanisms by which cytokines modulate ARNA in the DOCA-salt rat.
Specific Aim 2 : Define the anatomical substrates responsible for modulation of ARNA by immune mediators in DOCA-salt rats and mice.
Specific Aim 3 : Correlate the hemodynamic mechanisms mediating the anti-hypertensive response to ablation and pharmacological blockade of ARNA in DOCA-salt HTN, to urinary biomarkers of renal inflammation.
Specific Aim 4 : Employ a novel GCaMP3 mouse ex vivo renal slice preparation to identify molecular targets mediating cytokine modulation of afferent renal nerves in normal and DOCA-salt mice. Identification of the mechanisms by which immune cells interact with renal afferent nerves in HTN will also benefit understanding other renal inflammatory diseases with elevated SNA such as chronic renal failure.

Public Health Relevance

Hypertension (HTN) is the single leading cause of morbidity and mortality in the United States. The proposed research will aid in the development of new therapies that target the nerves to the kidney to reverse inflammation and HTN.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL116476-05A1
Application #
9661398
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2013-12-15
Project End
2022-10-31
Budget Start
2018-12-15
Budget End
2019-10-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Physiology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Osborn, John W; Banek, Christopher T (2018) Catheter-Based Renal Nerve Ablation as a Novel Hypertension Therapy: Lost, and Then Found, in Translation. Hypertension 71:383-388
Banek, Christopher T; Gauthier, Madeline M; Baumann, Daniel C et al. (2018) Targeted afferent renal denervation reduces arterial pressure but not renal inflammation in established DOCA-salt hypertension in the rat. Am J Physiol Regul Integr Comp Physiol 314:R883-R891
Fink, Gregory D; Phelps, Jeremiah T (2017) Can we predict the blood pressure response to renal denervation? Auton Neurosci 204:112-118
Banek, Christopher T; Knuepfer, Mark M; Foss, Jason D et al. (2016) Resting Afferent Renal Nerve Discharge and Renal Inflammation: Elucidating the Role of Afferent and Efferent Renal Nerves in Deoxycorticosterone Acetate Salt Hypertension. Hypertension 68:1415-1423
Foss, Jason D; Fink, Gregory D; Osborn, John W (2016) Differential role of afferent and efferent renal nerves in the maintenance of early- and late-phase Dahl S hypertension. Am J Physiol Regul Integr Comp Physiol 310:R262-7
Asirvatham-Jeyaraj, Ninitha; Fiege, Jessica K; Han, Ruijun et al. (2016) Renal Denervation Normalizes Arterial Pressure With No Effect on Glucose Metabolism or Renal Inflammation in Obese Hypertensive Mice. Hypertension 68:929-36
Xiao, Liang; Kirabo, Annet; Wu, Jing et al. (2015) Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II-Induced Hypertension. Circ Res 117:547-57
Foss, Jason D; Wainford, Richard D; Engeland, William C et al. (2015) A novel method of selective ablation of afferent renal nerves by periaxonal application of capsaicin. Am J Physiol Regul Integr Comp Physiol 308:R112-22
Averina, Viktoria A; Othmer, Hans G; Fink, Gregory D et al. (2014) A mathematical model of salt-sensitive hypertension: the neurogenic hypothesis. J Physiol :
Schlaich, Markus; Esler, Murray; Fink, Greg et al. (2014) Response to more research is needed to investigate the effect of denervation on blood pressure. Hypertension 63:e86

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