TRPV1 Activation Prevents Renal Ischemia-Reperfusion Injury-Induced Increase in Salt Sensitivity by Suppressing Renal Sympathetic Nerve Activity

Author(s): Shuang-Quan Yu, Shuangtao Ma, Donna H. Wang*

Journal Name: Current Hypertension Reviews

Volume 16 , Issue 2 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Salt sensitivity is increased following renal Ischemia-Reperfusion (I/R) injury. We tested the hypothesis that high salt intake induced increase in Renal Sympathetic Nerve Activity (RSNA) after renal I/R can be prevented by activation of Transient Receptor Potential Vanilloid 1 (TRPV1).

Methods: Rats were fed a 0.4% NaCl diet for 5 weeks after renal I/R, followed by a 4% NaCl diet for 4 more weeks in four groups: sham, I/R, I/R +High Dose Capsaicin (HDC), and I/R+Low Dose Capsaicin (LDC). The low (1mg/kg) or high (100mg/kg) dose of capsaicin was injected subcutaneously before I/R to activate or desensitize TRPV1, respectively.

Results: Systolic blood pressure was gradually elevated after fed on a high-salt diet in the I/R and I/R+HDC groups but not in the I/R+LDC group, with a greater increase in the I/R+HDC group. Renal function was impaired in the I/R group and was further deteriorated in the I/R+HDC group but was unchanged in the I/R+LDC group. At the end of high salt treatment, afferent renal nerve activity in response to unilateral intra-pelvic administration of capsaicin was decreased in the I/R group and was further suppressed in the I/R+HDC group but was unchanged in the I/R+LDC group. RSNA in response to intrathecal administration of muscimol, a selective agonist of GABA-A receptors, was augmented in the I/R group and further intensified in the I/R+HDC group but was unchanged in the I/R+LDC group. Similarly, urinary norepinephrine levels were increased in the I/R group and were further elevated in the I/R+HDC group but unchanged in the I/R+LDC group.

Conclusion: These data suggest that TRPV1 activation prevents renal I/R injury-induced increase in salt sensitivity by suppressing RSNA.

Keywords: TRPV1, blood pressure, renal ischemia/reperfusion, salt intake, sympathetic nervous system, capsaicin.

Kjellstrand CM, Ebben J, Davin T. Time of death, recovery of renal function, development of chronic renal failure and need for chronic hemodialysis in patients with acute tubular necrosis. Trans Am Soc Artif Intern Organs 1981; 27: 45-50.
[PMID: 7331111]
Bonomini V, Stefoni S, Vangelista A. Long-term patient and renal prognosis in acute renal failure. Nephron 1984; 36(3): 169-72.
[] [PMID: 6700808]
Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol 2001; 281(5): F887-99.
[] [PMID: 11592947]
Spurgeon-Pechman KR, Donohoe DL, Mattson DL, Lund H, James L, Basile DP. Recovery from acute renal failure predisposes hypertension and secondary renal disease in response to elevated sodium. Am J Physiol Renal Physiol 2007; 293(1): F269-78.
[] [PMID: 17507599]
Pechman KR, Basile DP, Lund H, Mattson DL. Immune suppression blocks sodium-sensitive hypertension following recovery from ischemic acute renal failure. Am J Physiol Regul Integr Comp Physiol 2008; 294(4): R1234-9.
[] [PMID: 18256138]
Pechman KR, De Miguel C, Lund H, Leonard EC, Basile DP, Mattson DL. Recovery from renal ischemia-reperfusion injury is associated with altered renal hemodynamics, blunted pressure natriuresis, and sodium-sensitive hypertension. Am J Physiol Regul Integr Comp Physiol 2009; 297(5): R1358-63.
[] [PMID: 19710386]
Philipp T, Distler A, Cordes U. Sympathetic nervous system and blood-pressure control in essential hypertension. Lancet 1978; 2(8097): 959-63.
[] [PMID: 81987]
Cowley AW Jr. Long-term control of arterial blood pressure. Physiol Rev 1992; 72(1): 231-300.
[] [PMID: 1731371]
Thrasher TN. Baroreceptors, baroreceptor unloading, and the long-term control of blood pressure. Am J Physiol Regul Integr Comp Physiol 2005; 288(4): R819-27.
[] [PMID: 15793035]
Koomans HA, Blankestijn PJ, Joles JA. Sympathetic hyperactivity in chronic renal failure: a wake-up call. J Am Soc Nephrol 2004; 15(3): 524-37.
[] [PMID: 14978154]
Boero R, Pignataro A, Ferro M, Quarello F. Sympathetic nervous system and chronic renal failure. Clin Exp Hypertens 2001; 23(1-2): 69-75.
[] [PMID: 11270590]
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature 1997; 389(6653): 816-24.
[] [PMID: 9349813]
Caterina MJ, Leffler A, Malmberg AB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000; 288(5464): 306-13.
[] [PMID: 10764638]
Avelino A, Cruz C, Nagy I, Cruz F. Vanilloid receptor 1 expression in the rat urinary tract. Neuroscience 2002; 109(4): 787-98.
[] [PMID: 11927161]
Wang DH, Li J, Qiu J. Salt-sensitive hypertension induced by sensory denervation: Introduction of a new model. Hypertension 1998; 32(4): 649-53.
[] [PMID: 9774358]
Wang DH, Li J. Antihypertensive mechanisms underlying a novel salt-sensitive hypertensive model induced by sensory denervation. Hypertension 1999; 33(1 Pt 2): 499-503.
[] [PMID: 9931155]
Wang DH, Wu W, Lookingland KJ. Degeneration of capsaicin-sensitive sensory nerves leads to increased salt sensitivity through enhancement of sympathoexcitatory response. Hypertension 2001; 37(2 Pt 2): 440-3.
[] [PMID: 11230315]
Huang Y, Wang DH. Role of renin-angiotensin-aldosterone system in salt-sensitive hypertension induced by sensory denervation. Am J Physiol Heart Circ Physiol 2001; 281(5): H2143-9.
[] [PMID: 11668076]
Ye DZ, Wang DH. Function and regulation of endothelin-1 and its receptors in salt sensitive hypertension induced by sensory nerve degeneration. Hypertension 2002; 39(2 Pt 2): 673-8.
[] [PMID: 11882629]
Wang DH, Zhao Y. Increased salt sensitivity induced by impairment of sensory nerves: Is nephropathy the cause? J Hypertens 2003; 21(2): 403-9.
[] [PMID: 12569272]
Li J, Wang DH. High-salt-induced increase in blood pressure: Role of capsaicin-sensitive sensory nerves. J Hypertens 2003; 21(3): 577-82.
[] [PMID: 12640252]
Song WZ, Chen AF, Wang DH. Increased salt sensitivity induced by sensory denervation: Role of superoxide. Acta Pharmacol Sin 2004; 25(12): 1626-32.
[PMID: 15569407]
Wang Y, Chen AF, Wang DH. Enhanced oxidative stress in kidneys of salt-sensitive hypertension: Role of sensory nerves. Am J Physiol Heart Circ Physiol 2006; 291(6): H3136-43.
[] [PMID: 16920809]
Zhu Y, Xie C, Wang DH. TRPV1-mediated diuresis and natriuresis induced by hypertonic saline perfusion of the renal pelvis. Am J Nephrol 2007; 27(5): 530-7.
[] [PMID: 17717412]
Xie C, Sachs JR, Wang DH. Interdependent regulation of afferent renal nerve activity and renal function: Role of transient receptor potential vanilloid type 1, neurokinin 1, and calcitonin gene-related peptide receptors. J Pharmacol Exp Ther 2008; 325(3): 751-7.
[] [PMID: 18364471]
Xie C, Wang DH. Ablation of transient receptor potential vanilloid 1 abolishes endothelin-induced increases in afferent renal nerve activity: mechanisms and functional significance. Hypertension 2009; 54(6): 1298-305.
[] [PMID: 19858408]
Xie C, Wang DH. Effects of a high-salt diet on TRPV-1-dependent renal nerve activity in Dahl salt-sensitive rats. Am J Nephrol 2010; 32(3): 194-200.
[] [PMID: 20639627]
Xie C, Wang DH. Inhibition of renin release by arachidonic acid metabolites, 12(s)-HPETE and 12-HETE: role of TRPV1 channels. Endocrinology 2011; 152(10): 3811-9.
[] [PMID: 21846804]
Yu SQ, Ma S, Wang DH. Activation of TRPV1 prevents salt-induced kidney damage and hypertension after renal ischemia-reperfusion injury in rats. Kidney Blood Press Res 2018; 43(4): 1285-96.
[] [PMID: 30078015]
Zhong B, Wang DH. N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1. Am J Physiol Heart Circ Physiol 2008; 295(2): H728-35.
[] [PMID: 18567714]
Dembiński A, Warzecha Z, Ceranowicz P, et al. Stimulation of sensory nerves and CGRP attenuate pancreatic damage in ischemia/reperfusion induced pancreatitis. Med Sci Monit 2003; 9(12): BR418-25.
[PMID: 14646970]
Ueda K, Tsuji F, Hirata T, Takaoka M, Matsumura Y. Preventive effect of TRPV1 agonists capsaicin and resiniferatoxin on ischemia/reperfusion-induced renal injury in rats. J Cardiovasc Pharmacol 2008; 51(5): 513-20.
[] [PMID: 18460982]
Mizutani A, Okajima K, Murakami K, et al. Activation of sensory neurons reduces ischemia/reperfusion-induced acute renal injury in rats. Anesthesiology 2009; 110(2): 361-9.
[] [PMID: 19194162]
Ueda K, Tsuji F, Hirata T, et al. Preventive effect of SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel transient receptor potential vanilloid 1 agonist, on ischemia/reperfusion-induced renal injury in rats. J Pharmacol Exp Ther 2009; 329(1): 202-9.
[] [PMID: 19147859]
Gram DX, Ahrén B, Nagy I, et al. Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes. Eur J Neurosci 2007; 25(1): 213-23.
[] [PMID: 17241282]
Demirbilek S, Ersoy MO, Demirbilek S, et al. Small-dose capsaicin reduces systemic inflammatory responses in septic rats. Anesth Analg 2004; 99(5): 1501-7.[table of contents.].
[] [PMID: 15502055]
Wang Y, Kaminski NE, Wang DH. VR1-mediated depressor effects during high-salt intake: Role of anandamide. Hypertension 2005; 46(4): 986-91.
[] [PMID: 16144988]
Wang Y, Wang DH. A novel mechanism contributing to development of Dahl salt-sensitive hypertension: Role of the transient receptor potential vanilloid type 1. Hypertension 2006; 47(3): 609-14.
[] [PMID: 16365187]
Yu SQ, Wang DH. Enhanced salt sensitivity following shRNA silencing of neuronal TRPV1 in rat spinal cord. Acta Pharmacol Sin 2011; 32(6): 845-52.
[] [PMID: 21642952]
Wu MS, Chien CT, Ma MC, Chen CF. Protection of ischemic preconditioning on renal neural function in rats with acute renal failure. Chin J Physiol 2009; 52(5): 365-75.
[] [PMID: 20359127]
Ma MC, Huang HS, Wu MS, Chien CT, Chen CF. Impaired renal sensory responses after renal ischemia in the rat. J Am Soc Nephrol 2002; 13(7): 1872-83.
[] [PMID: 12089383]
Raisinghani M, Pabbidi RM, Premkumar LS. Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin. J Physiol 2005; 567(Pt 3): 771-86.
[] [PMID: 16037081]

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 02 September, 2020
Page: [148 - 155]
Pages: 8
DOI: 10.2174/1573402115666191112122339

Article Metrics

PDF: 35