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Endothelin 1 (ET-1) and its receptors, ETA and ETB, play an important role in regulating renal function and blood pressure, and these components are expressed in sensory nerves. Activation of transient receptor potential vanilloid 1 (TRPV1) channels expressed in sensory nerves innervating the renal pelvis enhances afferent renal nerve activity (ARNA), diuresis, and natriuresis. We test the hypothesis that ET1 increases ARNA via activation of ETB, whereas ETA counter-balances ETB in wild type (WT) but not TRPV1-null mutant (TRPV−/−) mice. ET-1 alone or with BQ123, an ETA antagonist, perfused into the left renal pelvis increased ipsilaterel ARNA in WT but not TRPV−/− mice, and ARNA increases were greater in the latter. [Ala1, 3,11,15]-endothelin 1 (4 Ala-ET-1), an ETB agonist, increased ARNA that was greater than that induced by ET-1 in WT mice only. 4 Ala-ET-1-induced increases in ARNA were abolished by chelerythrine (CHE), a protein kinase C (PKC) inhibitor, but not by H89, a protein kinase A (PKA) inhibitor. Neither CHE, H89, nor BQ788, an ETB antagonist, affected ARNA triggered by capsaicin (CAP) in WT mice. Substance P (SP) release from the renal pelvis was increased by 4 Ala-ET-1 in WT mice only, and the increase was abolished by CHE but not by H89. Neither CHE, H89, nor BQ788 affected CAP-induced SP release. Our data show that ET1 increases ARNA via activation of ETB whereas ETA counter-balances ETB in WT but not TRPV−/− mice, suggesting that TRPV1 mediates ETB-dependent increases in ARNA, diuresis, and natriuresis via possibly the PKC pathway.
The transient receptor potential vanilloid type 1 (TRPV1) channels is mainly expressed in sensory nerves of unmyelinated C-fibers or thinly myelinated Aδ-fibers that innervate the cardiovascular as well as kidney tissues1. Activation of TRPV1 causes release of a variety of sensory neuropeptides including substance P (SP) and calcitonin gene-related peptide (CGRP), which have profound effects on modulation of cardiovascular and renal function (Figure 1)1–3. For example, the renal pelvis is densely innervated by TRPV1-positive sensory nerves4. 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 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 is dependent on TRPV1-mediated SP release and subsequent SP activation of the neurokinin 1 (NK1) receptors expressed in sensory nerves6–8. Given the important role of TRPV1 in mediating renal function, deletion of TRPV1 results in the loss of protection against renal injury9. Indeed, ablation of TRPV1 exaggerates renal functional and tissue damage induced by deoxycorticosterone acetate-salt (DOCA-salt) hypertension9.
Endothelin 1 (ET-1), a potent vasoconstrictor, is found as a neurotransmitter in primary afferent neurons and their nerve terminals10. 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 ganglia11. 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 deprivation12. 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 neurons13. In HEK293 cells, ET-1-induced potentiation of TRPV1 action depends on activation of ETA but not ETB via a protein kinase C (PKC)-dependent pathway13. Moreover, activation of TRPV1 via the ETA-PKC pathway contributes to ET-1-induced thermal hyperalgesia14.
Despite the fact that TRPV1 and the components of the ET-1 system are co-expressed in primary afferent nerves and the fact that activation of ETB expressed in renal tubules mediates ET-1-induced diuresis and natriuresis15–18, it is unknown whether TRPV1 plays a role in ET-1-induced changes in renal function. Understanding the interaction between TRPV1 and the ET1 system may provide insight into the mechanism underlying ET-1 mediated pathological changes in diseases and may identify downstream targets for drug development. The present study tests the hypothesis that 1) ET-1 perfusion into the renal pelvis increases ARNA in wild type (WT) but not TRPV1-null mutant (TRPV−/−) mice; 2) ET1-induced increases in ARNA are mediated by activation of ETB, whereas ETA plays a counter-balance role, in WT but not TRPV−/− mice; and 3) ETB-mediated increases in ARNA are via activation of the PKC but not PKA pathway in WT but not TRPV−/− mice (Figure 1).
All experimental protocols were approved by the Institutional Animal Care and Use Committee of Michigan State University. Ten-week-old male TRPV1−/− strain B6.129S4-TRPV1tm1Jul and C57BL/6 mice (WT) (the Jackson Laboratories, Bar Harbor, ME) were used in the experiments (total 170 mice). Mice were anesthetized by intraperitoneal administration of pentobarbital sodium at 50mg/kg. A PE-10 catheter was inserted into the left carotid artery for monitoring mean arterial pressure (MAP) with a Statham 231D pressure transducer coupled to a Gould 2400s recorder (Gould Instrument Systems, Valley View, Ohio, USA). Two MD-2000 microdialysis tubes (ID 0.18/OD 0.22 mm, BASi, West Lafayette, IN) were bond together and placed inside the left ureter via a midline incision. One of the tubes, whose tip extended 1–2 mm into the renal pelvis comparing to the other, was used for drug perfusion while the other for urine draining. The perfusion was performed at a rate of 20 µl/min at which the pelvis pressure did not change, and the drugs were perfused into the renal pelvis for 3min for ARNA measurement6. Mice were given the following treatments (n=5–6 in each group): (1) 10−8 M or 10−7 M ET-1 (Sigma-aldrich) perfused into the left renal pelvis of WT mice; (2) 10−7 M ET-1 with or without 5x10−6 M BQ123 (Sigma-aldrich), a selective ETA antagonist, given into the renal pelvis in WT and TRPV1−/− mice; (3) 10−7 M [Ala1, 3,11,15]-endothelin 1 (4 Ala-ET-1, Sigma-aldrich), a selective ETB agonist, given into the renal pelvis of WT and TRPV1−/− mice; (4) 4x10−6 M BQ788 (Sigma-aldrich), a selective ETB antagonist, with 4x10−6 M CAP administrated into the renal pelvis of WT mice; (5) 10−5 M chelerythrine (CHE, Tocris), a PKC inhibitor, given with 10−7 M 4 Ala-ET-1 or 4x10−6 M CAP into the renal pelvis of WT mice; (6) 2x10−5 M H89 (Sigma-aldrich), a PKA inhibitor, given with 10−7 M 4 Ala-ET-1 or 4×10−6 M CAP into the renal pelvis of WT mice.
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 platinum electrodes to record multifiber nerve activity. The electrode was connected to a high-impedance probe (HIP-511, Grass Instruments). The signals were amplified x20,000, filtered with a high-frequency cutoff at 1,000Hz and a low-frequency cutoff at 100Hz by a Grass model P511 AC amplifier, and recorded by a Gould 2400s recorder (Grould Instrument System, Valley View, Ohio, USA). 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 & Kwik-Sil (World Precision Instruments, Sarasota, Florida, USA).
The renal nerve activity was transformed into voltage integration. The experiment started 30min after the surgery. Basal value of ARNA was recorded 10min before the treatment and the recovery value of ARNA was recorded 10min after the treatment. The post-mortem renal nerve activity recorded as background of renal nerve activity was subtracted from all values. Average responses of ARNA were used for analysis and ARNA expressed in percent of its basal value6, 19.
The renal pelvis wall was removed from anesthetized mice and incubated in 37°C HEPES buffer (HEPES 25 mmol/L, NaCl 135 mmol/L, KCl 3.5 mmol/L, CaCl2 2.5 mmol/L, MgCl2 1 mmol/L, d-glucose 3.3 mmol/L, and 0.1 mmol/L ascorbic acid, pH 7.45) with 95%O2/5%CO2. The pelvis was incubated with drugs for 1h after it was equilibrated in the HEPES buffer for 30min. The incubation solution was collected and measured by radioimmunoassay (rat RIA kits; Peninsula Laboratories Inc, San Carlos, CA) as described previously and the SP concentration normalized by kidney weight20.
Frozen kidney sections obtained from WT and TRPV−/− mice were fixed with formalin for 15min and washed with PBS-0.01% Tween 20 for 5min. After blocking non-specific binding sites with 5% normal donkey serum for 30min, tissues were incubated with goat anti-TRPV1 (1:100, Santa Cruz), rabbit anti-ETB receptor (1:200, Santa Cruz), or rabbit anti-ETA receptor (1:200, Santa Cruz) diluted with 5% normal donkey serum at 4°C overnight whereas negative controls incubated with serum overnight only. The sections were rinsed with PBS-0.01% Tween 20 and incubated with donkey-anti-goat FITC-labeled IgG or donkey-anti-rabbit Cy3-labeled IgG for 1 hour at room temperature. The sections were washed, dehydrated with 95% and 100% ethanol, and covered with anti-fade mounting medium and coverslips21. In the double immunoflourescence staining study, the sections were incubated with the mixture of primary antibodies overnight at 4°C and then incubated with the mixture of secondary antibodies after rinse21, 22.
All values were expressed as means±SE. The differences of ARNA among groups were analyzed using one-way ANOVA followed by the Tukey-Kramer multiple comparison tests. The unpaired student’s t-test was used to determine the difference of SP levels between groups. Differences were considered statistically significant at p < 0.05.
There was no difference in the body weight between WT (29.4 ± 0.5g) and TRPV−/− (28.8 ± 0.6g) mice in all groups. The MAP between WT (95 ± 6 mmHg) and TRPV1−/− (97 ± 4 mmHg) mice was not statistically difference and it maintained at these levels before, during and after the treatments.
To examine the role of ET-1 in the regulation of ARNA in WT and TRPV1−/− mice, ET-1 was perfused into the left renal pelvis. Ipsilateral ARNA was increased by ET-1 perfusion at the concentrations of 10−8M (119 ± 9%, p<0.05) or 10−7M (136 ± 11%, p<0.01) in WT mice (Fig. 2). In contrast, ARNA was not altered (Fig. 2, 99 ± 11%, p>0.05) even when the higher dose of ET-1 (10−7M) was perfused into the left renal pelvis in TRPV1−/− mice.
To examine the role of the ETA receptor in ET-1-induced increases in ARNA, an ETA receptor antagonist, BQ123, was perfused into the left renal pelvis with or without 10−7M ET-1. BQ123 alone did not change ARNA in WT (Fig. 3, 106 ± 7%, p>0.05) or TRPV1−/− (98 ± 8%, p>0.05) mice. BQ123 combined with ET-1 perfusion into the left renal pelvis increased ARNA to 166 ± 18% in WT mice (Fig. 3, p<0.01), but it had no effect on ARNA in TRPV1−/− mice (105 ± 13%, p>0.05). Furthermore, the increase in ARNA induced by BQ123 plus 10−7M ET-1 (Fig. 3, 166 ± 18%) was higher than that induced by 10−7M ET-1 along (Fig. 2, 136 ± 11%) in WT mice (p<0.05).
To examine the role of the ETB receptor in the regulation of ARNA in WT and TRPV1−/− mice, an ETB receptor agonist, 4 Ala-ET-1, was perfused into the left renal pelvis. 4 Ala-ET-1 increased ARNA in WT (Fig. 4, 177 ± 35%, p<0.01) but not in TRPV1−/− (106 ± 18%, p>0.05) mice. Moreover, the increase in ARNA induced by 10−7M 4 Ala-ET-1 (Fig. 4, 177 ± 35%) was higher than that induced by 10−7M ET-1 (Fig. 2, 136 ± 11%) in WT mice (p<0.05). To determine whether the ETB receptor mediates CAP-induced increases in ARNA, an ETB receptor antagonist, BQ788, was perfused into the left renal pelvis with or without CAP. CAP increased ARNA (Fig. 4, 201 ± 21%, p<0.01) in WT mice. CAP combined with BQ788 also increased ARNA (202 ± 23%, p<0.01) in WT mice, but the magnitude of the increases in ARNA was the same between CAP alone and CAP plus BQ788 (p>0.05).
To examine the role of PKC and protein kinase A (PKA) in ETB-induced increases in ARNA in WT mice, PKC or PKA inhibitors were perfused into the left renal pelvis with or without the ETB receptor agonist. The PKC inhibitor, CHE, perfused alone did not alter ARNA (Fig. 5, 102 ± 9%, p>0.05) in WT mice. However, CHE abolished 4 Ala-ET-1-induced increases in ARNA (Fig. 5, 109 ± 4%, p>0.05) in WT mice. In contrast, CHE had no effect on CAP–induced increases ARNA (200 ± 23%, p<0.01). The PKA inhibitor, H89, perfused alone did not alter ARNA (Fig. 6, 105 ± 11%, p>0.05) in WT mice. Neither 4 Ala-ET-1-nor CAP-induced increases in ARNA were affected by H89 (Fig. 6, 173 ± 19%; and 199 ± 14%, p<0.01, respectively).
Radioimmunoassay was used to determine the level of SP released from the renal pelvis incubated in vitro (Fig. 7). The SP levels were not different between WT and TRPV1−/− mice at the baseline (0.57 ± 0.15 pg/g/min vs 0.57 ± 0.18pg/g/min, p>0.05, respectively), treated with ET-1 alone (0.59 ± 0.13 pg/g/min vs 0.66 ± 0.10 pg/g/min, p>0.05, respectively), or treated with BQ123 combined with ET-1 (0.72 ± 0.23pg/g/min vs 0.67 ± 0.11pg/g/min, p>0.05, respectively). 4 Ala-ET-1 alone increased SP release in WT (0.83 ± 0.10pg/g/min vs 0.57 ± 0.15 pg/g/min, p<0.05) but not in TRPV1−/− (0.58 ± 0.13pg/g/min vs 0.57 ± 0.18pg/g/min, p>0.05) mice compared to their respectively baselines. 4 Ala-ET-1-induced SP release in WT mice was abolished by CHE (0.83 ± 0.10pg/g/min vs 0.58 ± 0.07pg/g/min, p<0.05) but not by H89 (0.83 ± 0.10pg/g/min vs 0.81 ± 0.08pg/g/min, p>0.05). CAP increased SP release (0.84 ± 0.26pg/g/min vs 0.57 ± 0.15 pg/g/min, p<0.05) compared to the baseline in WT mice, and CAP-induced increases in SP release in WT mice were not affected by BQ788 (0.85 ± 0.16pg/g/min), CHE (0.92 ± 0.11pg/g/min), or H89 (0.90 ± 0.21pg/g/min).
Immunofluorescence staining was performed to determine the expression and co-expression of TRPV1, ETA, and ETB receptors in the renal pelvis of WT and TRPV−/− mice. TRPV1-positive nerve fibers were detected in the epithelial layer in the pelvis wall of WT but not TRPV1−/− mice (Fig. 8). ETA staining was not observed in the renal pelvis wall in either WT or TRPV1−/− mice. In contrast, ETB expressed in nerve fibers innervating the epithelial layer of the renal pelvis in both WT and TRPV−/− mice (Fig. 8). Moreover, ETB colocalized with TRPV1 in the nerve fibers innervating the pelvis wall in WT mice.
It has been reported that urine ET-1 levels are much higher than that of plasma23. In normal rats, the plasma ET-1 level is at 28 ± 3 fmol/ml, whereas the ET-1 concentration in the urine is about 4.7 ± 0.3 pmol/24h and in the kidney tissue 2.6 fmol/mg protein24, 25. Evidence shows that little circulating ET-1 is excreted into the urine, and the most urinary ET is renal origin26. The preparation used in the present study, namely renal pelvis perfusion, allows renal afferent nerves exposing to perfused drugs similarly to urine. It has been shown that affinity of 4Ala-ET-1 binding to ETB is 1,700 times higher than that binding to ETA27. ET-1 induces vasocontraction with EC50 10−9 M, which is abolished by the ETA antagonist whereas 4Ala-ET-1 with a concentration up to > or = 10−6 M has no effect28. These data indicate that 4Ala-ET-1 is unlikely to activate the ETA receptor at a concentration lower than 10−6 M27, 28. Furthermore, ET-1 incubated with cultured juxtaglomerular cells (IC50 3x10−9 M) inhibits renin release, an effect that is mimicked by 10−6 M 4Ala-ET-1 but not affected by BQ12329. Taken together, these results provide rationales for the selection of doses of ET-1 and 4Ala-ET-1 used for renal pelvis perfusion that ensures effectiveness and avoids non-specific binding.
All the components of the ET-1 system, including ET-1, ETA, and ETB, have been found to express in the sensory nervous system11, 30. Ablation of ET-1 leads to an elevation in the resting renal sympathetic nerve activity (RSNA) and an attenuation in hypercapnia-induced increases in RSNA31, suggesting that endogenous ET-1 governs the basal and reflex control of RSNA. Moreover, ET-1 injected into the hind paw of rats induces pain that is transmitted by sensory nerve fibers expressing ETA and ETB, which play distinct roles in mediating the pain pathway 32, 33. The ETA-PKC pathway contributes to ET-1-induced thermal hyperalgesia14. In contrast, the ETB-PKC pathway contributes to ET-1-mediated, mechanical-induced hypernociception33. It has been shown that activation of ETA increases RSNA whereas activation of ETB inhibits RSNA34, 35. In contrast, activation of ETA expressed in the renal pelvis suppresses ARNA in low salt treated rats, whereas activation of ETB enhances ARNA in high salt fed rats12, 36. These studies indicate that the ET system also plays a key role in the control of sensory nerve function and function of organs/tissues innervated by sensory nerves. Our data show that ET-1 perfused into the renal pelvis increases ARNA in WT but not TRPV1−/− mice, indicating that ET-1-induced increases in ARNA require the presence or activation of TRPV1. In addition, activation of ETB increases ARNA and inhibition of ETA potentiates ET-1-induced increases in ARNA in WT but not TRPV1−/− mice. These results indicate that TRPV1 mediates ETB-induced increases and ETA-induced suppression of ARNA.
ET-1 may modulate renal sodium and urine excretion17, 37, 38, and this effect may be mediated by interaction with renal nerves37. An ETA and ETB antagonist, bosentan, given into the kidney causes a reduction in urine flow in both normal and hypertensive rats while bosentan-mediated decreases in renal excretory function are abolished after renal denervation37, indicating a role for ET-1 receptors expressed in renal nerves in the regulation of renal function. Furthermore, decreased expression of ET-1, ETA and ETB have been found in the kidney of spontaneously hypertension rats (SHR), where down-regulation of ETB may contribute to excessive sodium retention in SHR37. Indeed, ETB in the kidney is involved in ET-1-induced inhibitory effects on antidiuresis39. The ETB agonist, sarafotoxin (S6c), given into the kidney causes enhanced diuresis in anaesthetized dogs, while excretion of sodium and the glomerular filtration rate remain unchanged38. Activation of ARNA also results in diuresis and natriuresis40. It has been shown that increased renal pelvis perfusion pressure leads to activation of ipsilateral ARNA, which causes an inhibitory renorenal reflex and leads to diuresis and natriuresis via suppression of contralateral renal sympathetic nerve activity40, 41. Our previous data show that activation of TRPV-1 by capsaicin perfused into the unilateral renal pelvis leads to activation of ipsilateral ARNA and bilateral diuresis and natriuresis via renorenal reflex5, 6. Our data in the present study show that activation of ETB increases ARNA in WT but not TRPV1−/− mice, whereas blockade of ETB has no effect on capsaicin-induced increases in ARNA in WT mice. Taken together, these data indicate that TRPV1 mediates ETB-dependent increases in ARNA induced by ET-1, and thereby contributes to ETB-induced increases in sodium and water excretion.
The primary sequence of TRPV1 contains many putative phosphorylation sites, and PKC- and PKA-mediated phosphorylation of TRPV1 is critical for its functions14, 42–44. PKC-mediated phosphorylation of TRPV1 has been shown to increase TRPV1-mediated effects14, 42–44. Activation of PKC potentiates or sensitizes TRPV1 responses to heat, protons, or its agonists and increases TRPV1-mediated SP and CGRP release43, 44. PKC also participates in ET-1-induced pain sensation14, 33. Previous data show that activation of ETB by ET-1 leads to hypernociception induced by mechanical stimulation via activation of the PKC pathway33. Our data in the present study show that the PKC inhibitor but not the PKA inhibitor perfused into the renal pelvis abolishes ETB-induced increases in ARNA, whereas capsaicin-induced increases in ARNA are not affected by the PKC or PKA inhibitors. These data indicate that the ETB-PKC pathway mediates the ET-1 effect on activation of TRPV1 and ARNA.
SP release has been shown to be regulated by several factors 42, 45, and mechano-induced increases in ARNA and SP release are abolished when NK1 receptors45 or TRPV1 channels8 are blocked. Our previous data show that TRPV1-induced increases in ARNA and renal excretory function depend on NK1 receptor activation by SP upon its release6. Data in the present study show that SP release is elevated when ETB is activated in WT but not TRPV1−/− mice, which is abolished by the PKC but not PKA inhibitors whereas neither the PKC nor PKA inhibitors affect capsaicin-induced increases in SP release. Taken together, these data indicate that TRPV1 mediates ETB-induced increases in SP release that is PKC-dependent.
TRPV1 is mainly expressed in small- and medium-sized neurons in dorsal root and trigeminal ganglia, and is transported to both the central and peripheral terminals of these primary afferent neurons1. TRPV1 has been found primarily in unmyelinated C-fibers or thinly myelinated Aδ-fibers in peripheral1. TRPV1 containing sensory nerves heavily innervate the upper ureter, the pelvis wall presenting in between uroepithelial and smooth muscle layer, and in the tubular cells of distal tubules and collecting ducts in the cortex and medulla4, 6, 8. The data in the present study show that TRPV1 expresses in nerve fibers innervating the epithelial layer of the renal pelvis wall in WT but not TRPV1−/− mice. Similarly, both ETA and ETB have been found in medium- to large-sized neurons in the trigeminal ganglia11. In the kidney, ETA that mainly locates in glomeruli and renal vasculature15, 46, 47 mediates the cortical and medullary vasoconstriction15, 46. ETB that is mainly distributed in the renal tubules contributes to ET-1-induced water and sodium excretion15, 46. Our immunofluorescence data show that ETB, co-localized with TRPV1, expresses in nerve fibers innervating the renal pelvis wall in both WT and TRPV1−/− mice. The reason that ETA staining was undetectable is unknown at the present time. However, it is likely that the staining method was not sensitive enough for detecting low abundance of ETA expressed in the renal pelvis wall in WT and TRPV1−/− mice15, 46, 47.
In conclusion, the data in the present study show that deletion of TRPV1 abolishes ET-1-induced increases in ARNA and SP release that is via activation of ETB, whereas activation of ETA plays a counter-balancing role. Moreover, ETB-induced activation of TRPV1 is mediated through a PKC but not PKA pathway. These findings indicate for the first time that TRPV1 may govern or contribute to ETB-mediated control of water and sodium excretion in the kidney.
TRPV1-containing sensory nerves, when activated, regulate diuresis and natriuresis of the kidney5. Neonatal degeneration of this population of sensory nerves leads to increased salt-sensitivity and arterial pressure48. Similarly, ET-1 also plays an important role in regulating renal excretory function through activation of the ETB receptors49. Collecting duct-specific knockout of the ETB receptors causes sodium retention and hypertension18. The data in the present study indicate that TRPV1 co-localizes with ETB in sensory nerve fibers innervating the renal pelvis, mediates ETB-induced increases in ARNA, and therefore may contribute to ETB-governed renal excretory function that is sensory nerve dependent. The molecular interaction of ETB and TRPV1 depends on activation of the PKC-pathway. On the other hand, activation of ETA conveys an inhibitory role, which counter-balances ETB stimulatory action, in the regulation of ET-1 induced increases in ARNA. Thus, it is conceivable that, in the cases when single or multi-dysfunction(s) of components in the ETA or ETB-PKC-TRPV1 pathway in sensory nerves innervating the kidney occurs, it may lead to impaired renal sensory nerve function and disturbed sodium and water homeostasis as depicted in Figure 1.
SOURCES OF FUNDING:
This study was supported in part by National Institutes of Health (grants HL-57853, HL-73287, and DK67620) and a grant from The Michigan Economic Development Corporation.