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CARDIOVASCULAR
Department of Medicine (C.X., J.R.S., D.H.W.), the Neuroscience Program (C.X., D.H.W.), and the Cell & Molecular Biology Program (C.X., D.H.W.), Michigan State University, East Lansing, Michigan
Received January 9, 2008; accepted March 24, 2008.
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Abstract |
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; 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 perfused into the renal pelvis causes an increase in ARNA, which is blocked by a NK1 receptor antagonist (Gontijo et al., 1999). Whereas these studies demonstrate a relation between CGRP and SP, their contribution to TRPV1 action is unknown.
SP perfused into the renal pelvis increases ipsilateral ARNA, contralateral urine flow, and urine sodium excretion, which is abolished by NK1 receptor antagonists (Kopp and Smith, 1991; Lindberg and Dolata, 1993). Increases in renal pelvis pressure or bradykinin perfused into the renal pelvis cause an increase in ARNA, which is also blocked by the NK1 receptor antagonist CP-96,345 or abolished when SP release is blocked (Kopp and Smith, 1993; Kopp et al., 2000). Whereas these results show a relation between increased renal pelvis pressure, bradykinin, and NK1 activation by SP, the role of NK1 receptors in TRPV1-induced increases in ipsilateral ARNA and contralateral renal function is unknown. Thus, the goal of the present study was to define the molecular mechanisms of TRPV1-induced increases in ARNA and the relation between TRPV1, NK1, and CGRP receptors.
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Materials and Methods |
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Surgical Procedures. Anesthesia was induced via intraperitoneally administered pentobarbital sodium at 50 mg · kg-1 and maintained with an i.v. infusion of 10 mg · kg-1 h-1 at 50 µl · min-1. Polyethylene catheters (PE-50) were placed in the left jugular vein for infusion of pentobarbital sodium and in the left carotid artery to measure mean arterial pressure (MAP) with a Statham 231D pressure transducer coupled to a Gould 2400s recorder (Gould Instrument Systems, Valley View, OH). Two catheters (PE-50) were inserted into both of the ureters with their tips in the renal pelvis via midline incision for urine collection. A MD-2000 microdialysis tube (i.d. 0.18/o.d. 0.22 mm; BASi, West Lafayette, IN) was placed inside the PE-50 catheter with its tip extending 1 to 2 mm out of the PE-50 catheter for perfusion drugs at 20 µl · min-1, a rate that did not change renal pelvis pressure (Zhu et al., 2005, 2007).
For the ARNA recording experiments, the renal nerves were isolated at the angle between the abdominal aorta and the renal artery via a left flank incision with the use of a stereoscopic dissecting microscope. The nerves were placed on the bipolar stainless steel electrode to record multifiber nerve activity. The electrode was connected to a high-impedance probe (HIP-511; Grass Instruments, Quincy, MA). The signals were amplified x20,000, filtered with a high-frequency cutoff at 1000 Hz and a low-frequency cutoff at 100 Hz by a Grass model P511 AC Amplifier and recorded by Gould 2400s recorder (Gould Instrument System). After the renal nerve activity was verified using its pulse synchronous rhythmicity with the heartbeat, the nerves were sectioned and the distal part was placed on the electrode for ARNA recording. The electrode was fixed to the renal nerve with Kwik-Cast and Kwik-Sil (World Precision Instruments, Sarasota, FL). The renal nerve activity was transformed into voltage integration. The post mortem renal nerve activity recorded as background of renal nerve activity was subtracted from all values. ARNA is expressed in percentage of its basal value (Ma et al., 2002a,b; Zhu et al., 2007).
Left renal pelvis perfusion was performed after surgery. The rats were stabilized for 1.5 h before the experiment started. The drugs were perfused into the renal pelvis in two 3-min periods; i.e., capsazepine (CAPZ, 0.4 mM; Calbiochem, San Diego, CA) (Zhu et al., 2005), an antagonist of TRPV1; RP67580 (0.2 mM; Tocris Cookson Inc., Ellisville, MO) (Zhu et al., 2005) and L703,606 (10 µM; Sigma-Aldrich, St. Louis, MO), antagonists of NK1 receptors; or CGRP8-37 (0.32 µM; American Peptide Co., Inc., Sunnyvale, CA), an antagonist of CGRP receptors, were perfused within the 1st 3-min period, as well as CAP, SP, or CGRP (0.13 µM; Sigma-Aldrich) with or without the antagonists within the 2nd 3-min period following right after the 1st 3-min period. In the case when one of the drugs above was perfused alone (either agonists or antagonists alone), the other period was perfused with the vehicle. Urine samples were collected for three 10-min periods, i.e., 10 min before the beginning of the 1st 3-min period as baseline; 10 min starting at the beginning of the 2nd 3-min period; and 10 min following right after the 2nd 10-min period. Urine flow rate (Uflow) and urinary sodium excretion (UNa) were determined in the samples collected from the contralateral kidney. Urinary sodium excretion was measured as described previously using a flame photometer (Model IL 943; Instrumentation Laboratory, Lexington, MA), and Uflow and UNa were expressed per gram of kidney weight per minute (micromole/minute/gram) (Zhu et al., 2005, 2007).
Renal Pelvis SP and CGRP Release. To measure the release of SP and CGRP from the renal pelvis, 10 µM thiorphan (Sigma-Aldrich), an endopeptidase inhibitor, was perfused into the renal pelvis to reduce the catabolism of SP and CGRP (Ma et al., 2002a). The samples were collected in three 10-min periods in animals in which the ARNA was recorded and stored at -70°C for the following analysis of SP and CGRP levels (Ma et al., 2002a).
Radioimmunoassay. The urine samples from the left kidney were purified and analyzed by rat radioimmunoassay kits (Peninsula Laboratories Inc., San Carlos, CA) as described previously for the measurement of SP and CGRP release. The concentration of CGRP and SP was normalized by the kidney weight (Wang and Wang, 2004).
Immunofluorescence. Dorsal root ganglion (DRG from both sides, T8–L4) and the renal pelvis were collected from control rats and frozen in optimal cutting temperature and stored at -70°C. The tissue sections were fixed with formalin before the experiment. They were first incubated in phosphate-buffered saline contained 5% bovine serum albumin (BSA) for 30 min at room temperature to block nonspecific binding, and then the sections were incubated with rabbit anti-NK1 receptor antiserum (1:50; Sigma-Aldrich) with 2% BSA at 4°C overnight. The negative control sections were incubated with 5% BSA instead of anti-NK1 receptor antiserum at 4°C overnight. After being rinsed three times for 10 min, the sections were incubated with donkey-anti-rabbit CY2-labeled IgG (1:500; Jackson ImmunoResearch Laboratories Inc., West Grove, PA) for 1 h in room temperature. The sections were washed and viewed under microscope after incubation (Wang and Wang, 2004; Aline Boer et al., 2005).
Statistical Analysis. All values were expressed as means ± S.E. The differences among groups were analyzed using one-way analysis of variance followed by the Tukey-Kramer multiple comparison tests. Comparisons of MAP before and after administration of drugs were performed by the use of a paired t test. Differences were considered statistically significant at p < 0.05.
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Results |
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Change of Contralateral Uflow, UNa, and Ipsilateral ARNA from Each Group. Whereas CAP was perfused into the left renal pelvis at concentrations of 0.04, 0.4, and 4 nM, ipsilateral ARNA was increased dose-dependently (Fig. 1). No difference existed in the basal and recovery values among different groups. CAP at 4 nM was chosen to be used in the following experiments unless otherwise indicated. SP at 3.7, 7.4, and 14.8 nM also increases ipsilateral ARNA dose-dependently, which occurred immediately after SP applications (Fig. 2). There was no difference in the basal and recovery values among groups. SP at 7.4 nM was used in the following experiments unless otherwise indicated.
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To evaluate the effect of NK1 and CGRP receptor antagonists on CAP-induced increases in contralateral Uflow, UNa, and ipsilateral ARNA, RP67580, L703,606, or CGRP8-37 was preperfused into the left renal pelvis. Both of the two NK1 antagonists, RP67580 and L703,606, abolished the increase of contralateral Uflow, UNa, and ipsilateral ARNA induced by CAP, whereas the CGRP receptor antagonist, CGRP8-37, did not alter the CAP effect (Fig. 4). RP67580 and L703,606 also blocked the increase of SP-induced increase in ARNA (from 206 ± 12 to 108 ± 10% and from 206 ± 12 to 115 ± 13%, respectively, p < 0.01). These results indicate that CAP action is NK1 but not CGRP receptor-dependent.
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CGRP perfused into the left renal pelvis led to increases of contralateral Uflow, UNa, and ipsilateral ARNA, which were delayed by approximately 100 s (Fig. 5). CGRP-induced increases of contralateral Uflow, UNa, and ipsilateral ARNA were abolished by CAPZ preperfused into the left renal pelvis (Fig. 5), indicating that TRPV1 mediates CGRP action.
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Staining of the NK1 Receptor in DRG and the Renal Pelvis Nerve Fibers. To determine whether there are NK1 receptors expressed in DRG and the renal pelvis nerve fibers, immunofluorescence was performed. In DRG, immunoreactivity of NK1 receptor was seen in DRG neurons (Fig. 8A). In the renal pelvis, NK1 receptor-positive nerve fibers were found (Fig. 8C).
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Discussion |
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-fibers (Guo et al., 1999). Activation of TRPV1 leads to release of various neuropeptides, including SP and CGRP, both of which may increase ARNA (Kopp and Smith, 1991; Gontijo et al., 1999; Guo et al., 1999). The goal of the present study was to examine whether there was cross-talk between TRPV1, NK1, and CGRP receptors (Fig. 9). We have previously shown that CAP perfused into the renal pelvis leads to an increase in diuresis and natriuresis, which can be blocked by the TRPV1 antagonist, CAPZ, perfused into the renal pelvis or by ipsilateral denervation (Zhu et al., 2005). Furthermore, hypertonic saline-induced increases in ipsilateral ARNA and contralateral renal excretory function are mediated by activation of TRPV1 and NK1 receptors (Zhu et al., 2007). These data indicate that activation of TRPV1-positive sensory nerves innervating the renal pelvis leads to increases in ipsilateral ARNA and enhances contralateral renal excretory function. However, the role of endogenously released CGRP and SP in TRPV1-mediated actions is unknown.
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It has been shown that CGRP administered into the renal pelvis increases ARNA, which is blocked by the CGRP receptor antagonist CGRP8-37 (Gontijo and Kopp, 1999). However, the CGRP receptor antagonist is not effective in blocking the increase of ipsilateral ARNA, contralateral Uflow, and UNa induced by increases in renal pelvis pressure or by NaCl or KCl perfused into the renal pelvis (Gontijo and Kopp, 1999). Consistently, we have shown in the present experiment that the increase in ipsilateral ARNA, contralateral Uflow, and UNa induced by activation of TRPV1 is not blocked by the CGRP receptor antagonist, indicating that TRPV1, activated by altered physical or chemical environments in the renal pelvis, may function independent of CGRP receptor activation. Indeed, we have shown that TRPV1, when activated by hypertonic saline perfused into the renal pelvis, mediates hypertonic saline-induced natriuresis and diuresis (Zhu et al., 2007). It is intriguing that, in contrast to CGRP-independent effects of TRPV1, the increases of ipsilateral ARNA, contralateral Uflow, and UNa induced by CGRP perfused into the renal pelvis are blocked by the TRPV1 antagonist CAPZ. These data indicate that CGRP-induced increases in ipsilateral ARNA and contralateral renal excretion function depend on the activation of TRPV1. It has been shown that CGRP receptor activation activates phospholipase C (PLC), which involves the G
q/11 subunit of G-proteins (Drissi et al., 1998). CAP can also activate PLC in TRPV1-positive cells, and the activation of phosphoinositides leads to TRPV1 activation (Lukacs et al., 2007). Thus, the cross-talk between CGRP receptors and TRPV1 channels may mediate by PLC activation.
Increases in the renal pelvis pressure may cause an increase in ARNA, which can be blocked by the NK1 receptor antagonist CP-96,345 (Kopp and Smith, 1993). Increases in renal pelvis pressure lead to increases of ARNA and the release of prostaglandin E2 and SP in the ipsilateral renal pelvis (Kopp and Smith, 1993). Increases in ARNA are abolished when the release of prostaglandin E2 and SP is blocked (Kopp et al., 1996). This evidence indicates that the increase of ARNA induced by increase of the renal pelvis pressure depends on SP release and its activation of the NK1 receptor (Kopp and Smith, 1993; Kopp et al., 1996). Moreover, bradykinin perfused into the renal pelvis causes an increase in ARNA, and this response also depends on SP release and its activation of the NK1 receptor (Kopp et al., 2000). Our results show that CAP-induced increases in ipsilateral ARNA, contralateral Uflow, and UNa are blocked by the NK1 receptor antagonists RP67580 and L703,606. These data indicate that CAP activation of ARNA depends on activation of the NK1 receptor following SP release induced by CAP activation of TRPV1.
SP is a neuropeptide found in sensory nerves (Guo et al., 1999). SP given via renal pelvis perfusion causes an increase in ipsilateral ARNA and contralateral excretion function (Kopp and Smith, 1991; Ma et al., 2002b). Inhibition of Na-K-ATPase, which plays a role in maintaining membrane-resting potential, sensitizes renal mechanoreceptors activated by increases of renal pelvis pressure (Kopp et al., 1994). In contrast, the Na+ channel blocker, amiloride, given into the renal pelvis reduces the increase of ARNA triggered by increases in renal pelvis pressure or by SP administered into the renal pelvis (Kopp et al., 1998). SP produces a slow depolarization in respiratory pacemaker and nonpacemaker neurons, and the depolarization is induced by activating a low-threshold tetrodotoxin-insensitive cation channel that is mostly selective for Na+ (Peña and Ramirez, 2004). In cultured rat cortex neurons, a voltage-dependent sodium current activated by SP can be blocked by NK1 receptor antagonists (Caeser et al., 1993). Unlike Na-K-ATPase inhibitors or sodium channel blockers, our results indicated that the TRPV1 antagonist did not affect the increase of ipsilateral ARNA and contralateral excretion function induced by SP perfused into the renal pelvis, albeit the NK1 receptor antagonists abolish the increases in ARNA and renal excretory function caused by CAP. Taken together, these data indicate that the TRPV1-induced increases in ARNA and contralateral renal excretion function depend on SP-induced activation of NK1; i.e., NK1 activation by endogenously released SP governs TRPV1-mediated action. Furthermore, SP-induced increases in ARNA and renal function might be mediated by the activation of Na+ channels.
Our data show that CAP-induced CGRP and SP release from sensory nerves in ipsilateral renal pelvis was blocked by CAPZ preperfused into the renal pelvis, indicating a TRPV1-dependent mechanism. Although NK1 receptor antagonists given into the left renal pelvis did not block the release of CGRP and SP triggered by CAP, they did block CAP-induced increases in ipsilateral ARNA and contralateral renal excretion function. Neither CGRP and SP release nor ARNA and renal excretion function induced by CAP was altered by the CGRP receptor antagonist. Taken together, our data indicate that CAP-induced increases in ipsilateral ARNA and contralateral Uflow and UNa depend on activation of NK1 receptors following SP release.
In conclusion, these experiments show that activation of NK1 by endogenously released SP mediates TRPV1-induced increases in ipsilateral ARNA and contralateral renal excretion function, indicating that NK1 controls TRPV1 function. Furthermore, TRPV1 governs CGRP- but not SP-induced ipsilateral ARNA and contralateral renal excretion function, indicating a TRPV1-dependent mechanism of CGRP action.
Consistent with previous findings (Chen and Hoover, 1995), our immunofluorescence results show that NK1 receptors are located in both DRG neurons and the renal pelvic nerves, albeit specific cell localization is needed to be determined in the future. It has been shown that the reduction of NK1 receptors expressed in the renal pelvis might contribute to the impaired renorenal reflex in cirrhotic rat (Ma et al., 2002b). The decrease in functional NK1 receptors in the renal pelvis also plays a role in the impaired ARNA after renal ischemia (Ma et al., 2002c). Colocalization of the NK1 receptor, CGRP, and SP is found in DRG neurons, and the impaired ARNA in SHR rats may be related to the changes of SP and CGRP and/or to the decrease in NK1 receptors in DRG neurons (Aline Boer et al., 2005). Moreover, impaired expression and function of TRPV1 have been found in Dahl salt-sensitive hypertensive rats, which may contribute to the development of salt-induced increases in blood pressure in this strain (Wang and Wang, 2006). Taken together, the data of the present studies regarding the cross-talk between TRPV1, NK1, and CGRP receptors raise the possibility that impairment or dysfunction in these components may impair renal function and may contribute to disease state, such as hypertension.
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Footnotes |
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ABBREVIATIONS: TRPV1, transient receptor potential vanilloid type 1; ARNA, afferent renal nerve activity; NK1, neurokinin 1; CGRP, calcitonin gene-related peptide; SP, substance P; CAP, capsaicin; CAPZ, capsazepine; Uflow, urine flow rate; UNa, urinary sodium excretion; DRG, dorsal root ganglion; MAP, mean arterial pressure; BSA, bovine serum albumin; PLC, phospholipase C; CP-96,345, (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine; RP67580, 2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4-perhydroiso-indolone (3aR,7aR); L703,606, cis-2-(diphenylmethyl)-N-[(2-iodophenyl)methyl]-1 azabicyclo[2.2.2]octan-3-amine; CGRP8-37, C139H230N44O38, VTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH2.
Address correspondence to: Dr. Donna H. Wang, Department of Medicine, B338 Clinical Center, Michigan State University, East Lansing, MI 48824. E-mail: donna.wang{at}ht.msu.edu
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