Background: The transient receptor potential vanilloid type 1 (TRPV1) channel is known to be activated by multiple stimuli, albeit its role in mediating renal function is largely unknown. This study was designed to test the hypothesis that TRPV1 mediates diuresis and natriuresis induced by hypertonic saline perfusion into the pelvis. Methods: NaCl or KCl was perfused into the left renal pelvis of rats at a rate without changing renal pelvic pressure. Afferent renal nerve activity (ARNA), urine flow rate (V) and urinary sodium excretion (UNaV) in the presence or absence of selective antagonists of TRPV1, capsazepine (CAPZ), or neurokinin-1 (NK1) receptors, RP67580, were examined. Results: Unilateral renal pelvis perfusion of NaCl at 600 mM, but not 150 or 300 mM, increased ipsilateral ARNA and contralateral V and UNaV, which were blocked by ipsilateral administration of CAPZ or RP67580. In contrast, KCl perfused at 150 or 300 mM, but not 600 mM, increased ipsilateral ARNA and contralateral V and UNaV, which were insensitive to CAPZ. Conclusion: Unilateral hypertonic saline perfusion causes contralateral diuresis and natriuresis via TRPV1 or NK1 activation, indicating that these receptors may play a critical role in sensing microenvironmental changes in the renal pelvis to modulate renal function in health and disease.
Our previous studies have shown that the activation of the transient receptor potential vanilloid type 1 (TRPV1) expressed in the renal pelvis leads to an increase in ipsilateral afferent renal nerve activity (ARNA) and contralateral renal excretory function, but the molecular mechanisms of TRPV1 action are largely unknown. This study tests the hypothesis that activation of receptors of neurokinin 1 (NK1) or calcitonin gene-related peptide (CGRP) by endogenously released substance P (SP) or CGRP following TRPV1 activation, respectively, governs TRPV1-induced increases in ARNA and renal excretory function. Capsaicin (CAP; 0.04, 0.4, and 4 nM), a selective TRPV1 agonist, administered into the renal pelvis dose-dependently increased ARNA. CAP (4 nM)-induced increases in ipsilateral ARNA or contralateral urine flow rate (Uflow) and urinary sodium excretion (UNa) were abolished by capsazepine (CAPZ), a selective TRPV1 antagonist, or 2-[1-imino-2-(2-antagonists, but not by CGRP8-37, a selective CGRP receptor antagonist. Both SP (7.4 nM) and CGRP (0.13 M) increased ARNA, Uflow, or UNa, and increases in these parameters induced by CGRP but not SP were abolished by CAPZ. CAP at 4 nM perfused into the renal pelvis caused the release of SP and CGRP, which was blocked by CAPZ but not by RP67580, L703,606, or CGRP8-37. Immunofluorescence results showed that NK1 receptors were expressed in sensory neurons in dorsal root ganglion and sensory nerve fibers innervating the renal pelvis. Taken together, our data indicate that NK1 activation induced by SP release upon TRPV1 activation governs TRPV1 function and that a TRPV1-dependent mechanism is operant in CGRP action.The transient receptor potential vanilloid type 1 (TRPV1) channel is a nonselective cation channel that can be activated by capsaicin (CAP), noxious heat, lipid metabolites, and protons (Guo et al., 1999;Julius and Basbaum, 2001;Klionsky et al., 2006). Our previous data show that activation of TRPV1 by CAP perfused into the unilateral renal pelvis leads to bilateral diuresis and natriuresis via a dual renorenal reflex and that this effect is abolished after ipsilateral renal denervation (Zhu et al., 2005). Moreover, hypertonic saline perfused into the renal pelvis causes increases in ipsilateral afferent renal nerve activity (ARNA) and contralateral renal excretory function by activation of TRPV1 and neurokinin 1 (NK1) receptors (Zhu et al., 2007). These data indicate that TRPV1-positive sensory nerves innervating the renal pelvis play an important role in regulating ARNA and maintaining sodium and water homeostasis, but the mechanism by whichTRPV1 activation induces elevated ARNA is largely unknown.Activation of TRPV1 expressed in sensory nerves of unmyelinated C-fibers or thinly myelinated A␦-fibers causes release of a variety of sensory neuropeptides, including substance P (SP) and calcitonin gene-related peptide (CGRP). SP and CGRP are colocalized in renal pelvis sensory nerves and may be totally depleted after CAP treatment (Hua et al., 1987). CGRP perfu...
We test the hypothesis that 12-hydroperoxyeicosatetraenoic acid (12(s)-HPETE) and 12-hydroxyeicosatetraenoic acid (12-HETE) perfused into the renal pelvis increase afferent renal nerve activity (ARNA) and suppress renin release in rats fed a low-salt (LS) diet via activation of the transient receptor potential vanilloid type 1 (TRPV1) expressed in renal sensory nerves. 12(s)-HPETE or 12-HETE given into the left renal pelvis dose-dependently increased ARNA, which was abolished by AMG9810, a selective TRPV1 antagonist, or by RP67580, a selective neurokinin 1 receptor antagonist, in normal salt or LS-treated rats. 12(s)-HPETE, 12-HETE, or substance P perfused into the left renal pelvis suppressed plasma angiotensin I (Ang I) levels in LS rats, which was abolished by AMG9810 or attenuated by ipsilateral renal denervation (RD). 12(s)-HPETE or 12-HETE increased release of substance P and calcitonin gene-related peptide from the ipsilateral kidney, which was abolished by AMG9810 but not RP67580, RD, or RP67580 plus RD. Immunofluorescence staining showed that TRPV1-positive nerve fibers located in the renal cortex, medulla, and pelvis, and that the sympathetic nerve marker, neuropeptide Y, but not neurokinin 1 receptors expressed in the juxtaglomerular region colocalized with renin. Thus, our data show that 12(s)-HPETE and 12-HETE enhance ARNA and substance P/calcitonin gene-related peptide release but suppress renin activity in LS rats, and these effects are abolished when TRPV1 is blocked. These results indicate that TRPV1 mediates 12(s)-HPETE and 12-HETE action in the kidney in such a way that dysfunction in TRPV1 may lead to disintegrated regulation of renin and renal function.
Abstract-Endothelin 1 (ET-1) and its receptors, ETA and ETB, play important roles in regulating renal function and blood pressure, and these components are expressed in sensory nerves. Activation of transient receptor potential vanilloid (TRPV) 1 channels expressed in sensory nerves innervating the renal pelvis enhances afferent renal nerve activity (ARNA), diuresis, and natriuresis. We tested the hypothesis that ET-1 increases ARNA via activation of ETB, whereas ETA counterbalances ETB in wild-type (WT) but not TRPV1-null mutant mice. ET-1 alone or with BQ123, an ETA antagonist, perfused into the left renal pelvis increased ipsilateral ARNA in WT but not in TRPV1-null mutant mice, and ARNA increases were greater in the latter. [Ala1,3,11,15 Key Words: TRPV1 Ⅲ ET-1 Ⅲ ETB receptors Ⅲ PKC Ⅲ afferent renal nerve activity T he transient receptor potential vanilloid type 1 (TRPV1) channel is mainly expressed in sensory nerves of unmyelinated C-fibers or thinly myelinated A␦-fibers that innervate the cardiovascular and kidney tissues. 1 Activation of TRPV1 causes release of a variety of sensory neuropeptides, including substance P (SP) and calcitonin gene-related peptide, which have profound effects on the modulation of cardiovascular and renal function (Figure 1). 1-3 For example, the renal pelvis is densely innervated by TRPV1-positive sensory nerves. 4 Agonist-induced activation of TRPV1 expressed in the unilateral renal pelvis leads to increases in ipsilateral afferent renal nerve activity (ARNA) and contralateral urinary sodium and water excretion via the renorenal reflex, which can be abolished by renal denervation ( Figure 1). 5,6 Hypertonic saline perfusion of the renal pelvis or increased renal pelvis pressure as a mean of mechanostimulation may activate TRPV1, leading to increased ARNA and diuresis and natriuresis, a sequence of events that depends on TRPV1-mediated SP release and subsequent SP activation of the neurokinin 1 (NK1) receptors expressed in sensory nerves. 6 -8 Given the important role of TRPV1 in mediating renal function, deletion of TRPV1 results in the loss of protection against renal injury. 9 Indeed, ablation of TRPV1 exaggerates renal functional and tissue damage induced by deoxycorticosterone acetate-salt hypertension. 9 Endothelin 1 (ET-1), a potent vasoconstrictor, is found as a neurotransmitter in primary afferent neurons and their nerve terminals. 10 Immunocytochemistry results show that its receptor subtypes, endothelin A (ETA) and endothelin B (ETB) receptors, are present in medium-and large-sized cell bodies of human trigeminal ganglia. 11 In rats, ET-1 perfusion into the renal pelvis increases ARNA via activation of ETB when a high-salt diet is given and decreases ARNA via activation of ETA in the face of salt deprivation. 12 Colocalization of TRPV1 and ETA has been found in a subpopulation of primary sensory neurons, whereas ET-1 sensitizes capsaicin (CAP)-induced TRPV1 current in this population of neurons. 13 In HEK293 cells, ET-1-induced potentiation of TRPV1 action depends ...
Objective: To test the hypothesis that transient receptor potential vanilloid type 1 channel (TRPV1)-mediated increases in afferent renal nerve activity (ARNA) and release of substance P (SP) and calcitonin gene-related peptide (CGRP) from the renal pelvis are suppressed in Dahl salt-sensitive (DS), but not -resistant (DR), rats fed a high-salt (HS) diet. Methods and Results: Male DS and DR rats were given a HS or low-salt (LS) diet for 3 weeks. Perfusion of capsaicin (CAP, 10–6M), a selective TRPV1 agonist, into the left renal pelvis increased ipsilateral ARNA in all groups, but with a smaller magnitude in DS-HS compared to other groups. CAP increased contralateral urine flow in all groups except DS-HS rats. CAP-induced release of SP and CGRP from the renal pelvis was less in DS-HS compared to other groups. Western blot showed that TRPV1 expression in the kidney decreased while expression of neurokinin 1 receptors increased in DS-HS compared to other groups. Conclusion: TRPV1-mediated increases in ARNA and release of SP and CGRP in the renal pelvis are impaired in DS rats fed a HS diet, which can likely be attributed to suppressed TRPV1 expression in the kidney and contributes to increased salt sensitivity.
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