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. 2025 Nov 3;604(3):1415–1427. doi: 10.1113/JP289721

Deletion of the TRPV1 channel attenuates afferent renal nerve responses to renal artery occlusion but not elevated renal pelvic pressure

Jacob B Sullivan 1, Leon J DeLalio 1, Sean D Stocker 1,✉
PMCID: PMC12871925  PMID: 41185411

Abstract

Abstract

Renal sensory neurons widely express the transient receptor potential vanilloid type 1 (TRPV1). TRPV1 is a non‐selective cation channel responsive to mechanosensitive stimuli, temperature, pH and various chemical factors. The present study tested whether TRPV1 channels contribute to afferent renal nerve activity (ARNA) responses during renal artery occlusion, renal ischaemia and increased renal pelvic pressure using a Trpv1−/− rat with a 26‐bp deletion in exon 3. Both male and female wild‐type (WT) and Trpv1−/− littermates (8–12 weeks) were anaesthetized with Inactin and prepared for recording of ARNA and haemodynamics. First total renal artery occlusion (90 s) produced a biphasic ARNA response in WT rats characterized by an abrupt increase in ARNA at the onset of occlusion followed by a delayed and substantial increase in ARNA after 45 s. This delayed ARNA activation was significantly attenuated in Trpv1−/− rats. Second, graded reductions in renal blood flow (25%, 50% and 75%, 90 s) produced flow‐dependent increases in ARNA, but these responses did not differ between WT and Trpv1−/− rats. Third, increased renal pelvic pressure (5, 10 and 20 mmHg, 60 s) elevated ARNA in both strains; however, the magnitude of these responses did not differ between WT and Trpv1−/− rats. Altogether, these data suggest TRPV1 channels play distinct roles in renal interoception and ARNA activation, which include chemosensitive stimuli during prolonged renal artery occlusion but not mechanosensitive stimuli during increased renal pelvic pressure or acute reduction in renal blood flow.

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Key points

  • Renal artery occlusion produced a biphasic increase in afferent renal nerve activity (ARNA) of wild‐type (WT) rats with an initial increase at occlusion onset followed by a substantial increase 45 s later. This latter phase was significantly attenuated in Trpv1−/− rats.

  • Partial reductions in renal artery blood flow (75%, 50% and 25% of baseline) produced flow‐dependent increases in ARNA that were similar between WT and Trpv1−/− rats.

  • ARNA responses to elevated renal pelvic pressure did not differ between WT and Trpv1−/− rats.

  • Renal pelvic infusion of the TRPV1 antagonist capsazepine attenuated ARNA responses to elevated renal pelvic pressure in both WT and Trpv1−/− rats, suggesting actions of capsazepine independent of the TRPV1 channel.

  • These findings suggest TRPV1 channels play distinct roles in renal interoception and ARNA activation, which include chemosensitive stimuli during prolonged renal artery occlusion but not mechanosensitive stimuli during increased renal pelvic pressure or acute reduction in renal blood flow.

Keywords: afferent, chemoreceptor, ischaemia, mechanoreceptor, occlusion, pelvic pressure, TRPV1

Abstract figure legend Using wild‐type and Trpv1−/− rats, we assessed the contribution of TRPV1 channels to the activation of afferent renal nerve activity (ARNA) during renal artery occlusion, graded reductions in renal blood flow and elevated renal pelvic pressure. Trpv1−/− rats exhibited an attenuated ARNA activation to renal artery occlusion but not graded reductions in renal blood flow or elevated renal pelvic pressure.

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Introduction

Renal sensory nerves innervate the vasculature, renal tubules, glomeruli and pelvic wall (Ferguson & Bell, 1988; Ferguson et al., 1988; Kopp, 2015; Marfurt & Echtenkamp, 1991; Osborn et al., 2021). These afferents respond to both mechanosensitive and chemosensitive stimuli, including changes in renal perfusion pressure or ischaemia, local factors or chemicals (e.g. capsaicin, bradykinin, adenosine, hypertonic NaCl), and to increased pelvic pressure (DeLalio & Stocker, 2021; Katholi et al., 1983; Recordati et al., 1978; Recordati et al., 1980; Recordati et al., 1981). In turn these afferent fibres project centrally and reflexively alter efferent sympathetic nerve activity, renal function and arterial blood pressure (ABP) (Kopp, 2015; Osborn et al., 2021). Elevated afferent renal nerve activity (ARNA) or dysfunctional renal afferent nerves contribute to multiple experimental models of hypertension, chronic kidney disease and other pathophysiological models (Banek et al., 2016; Faber & Brody, 1985; Kopp & Buckley‐Bleiler, 1989; Kopp et al., 1987; Lopes et al., 2020; Marreiros et al., 2025; Ong et al., 2019; Sata et al., 2021; Stocker & Sullivan, 2023; Wyss et al., 1986).

The transient receptor potential vanilloid type 1 (TRPV1) channel is a non‐selective cation channel and responds to mechanosensitive stimuli, temperature, pH and various chemical factors (Julius, 2013; Nilius, 2007; Rosenbaum & Simon, 2007). TRPV1 is widely expressed in renal sensory neurons as approximately 85% of rat dorsal root ganglion (DRG) neurons projecting to the kidney are TRPV1 positive (Stocker & Sullivan, 2023). Intrapelvic or intrarenal artery infusion of the TRPV1 agonist capsaicin dose dependently increases ARNA (DeLalio & Stocker, 2021; Ditting et al., 2012; Feng et al., 2008; Stocker & Sullivan, 2023). Therefore TRPV1 may mediate diverse renal sensory processes in the kidney. Chemical ablation of TRPV1‐expressing fibres by 5‐day systemic treatment with capsaicin attenuated ARNA responses to elevated renal pelvic pressure or intrapelvic infusion of hypertonic NaCl (Kopp & Smith, 1991). However this approach does not distinguish between the contribution of TRPV1‐expressing fibres and the TRPV1 channel. In regard to the latter, renal intrapelvic administration of the TRPV1 antagonist capsazepine attenuated ARNA activation and contralateral diuresis/natriuresis to elevated renal pelvic pressure (Ditting et al., 2012; Feng et al., 2008). In addition, intrapelvic infusion of capsazepine attenuated ARNA activation to intrapelvic administration of hypertonic NaCl but not KCl (Zhu et al., 2007). Although these data support the hypothesis that TRPV1 channels contribute to ARNA activation during changes in renal pelvic pressure and stimulation with hypertonic NaCl, the observations rely only on pharmacological antagonism of TRPV1 using capsazepine. Capsazepine also interferes with additional targets, including but not limited to voltage‐gated calcium channels, nicotinic acetylcholine receptors, epithelial sodium channel and TRPVA1 (Behrendt et al., 2004; Bevan et al., 1992; Docherty et al., 1997; Kistner et al., 2016; Liu & Simon, 1997; Yamamura et al., 2004).

The aim of the present study was to determine the extent by which TRPV1 channels contribute to ARNA activation using a recently developed Trpv1−/− rat (Stocker & Sullivan, 2023). The Trpv1−/− rat has a 26‐bp deletion in exon 3 and exhibits a normal resting ABP and glomerular filtration rate but lacks expression of TRPV1 in the DRG and does not respond to capsaicin (Anselmi et al., 2023; Stocker & Sullivan, 2023). Here we report that Trpv1−/− rats exhibited attenuated ARNA responses to renal artery occlusion but normal ARNA responses to partial reductions in renal blood flow and renal pelvic pressure. Moreover intrapelvic administration of capsazepine attenuated ARNA responses to elevated renal pelvic pressure in both wild‐type (WT) and Trpv1−/− rats, thereby suggesting a non‐specific (and non‐TRPV1) effect.

Methods

Ethical approval

All of the experimental procedures conform to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee at the University of Pittsburgh School of Medicine (IACUC24085562). This research complies with the animal ethics checklist of The Journal of Physiology and ARRIVE guidelines.

Animals

Both male and female WT or Trpv1−/− littermates were produced by breeding heterozygous Trpv1+/− rats (SD‐Trpv1em4Mcwi ) produced by CRISPR‐Cas9 26‐bp deletion in exon 3 as described and validated previously (Stocker & Sullivan, 2023). Genotypes were determined using ear punch and PCR (Stocker & Sullivan, 2023), and rats were weaned between 24 and 28 days. Trpv1−/− rats have a normal resting ABP and kidney function but lack TRPV1 immunofluorescence in the DRG and do not respond to capsaicin (Anselmi et al., 2023; Stocker & Sullivan, 2023). WT and Trpv1−/− rats (8–12 weeks of age) were housed two to three per cage in a temperature‐controlled room (22 ± 1°C) with a 12‐h light–dark cycle (7:00 AM—7:00 PM lights turned off) and provided ad libitum access to LabDiets chow (5P76) and water. Experiments were conducted between 9:00 AM and 5:00 PM. All animals were euthanized using isoflurane (5% in 100% O2) and cardiac transection.

General experimental preparation

WT and Trpv1−/− littermates were initially anaesthetized with isoflurane (2%–3% in 100% O2), artificially ventilated and prepared for ARNA recordings as described previously (DeLalio & Stocker, 2021; Stocker & Sullivan, 2023). End‐tidal CO2 was measured continuously using a GEMINI Gas Respiratory Analyzer (CWE, Inc., Ardmore, PA, USA) maintained at 3.5%–4.5% by adjusting the ventilation rate (60–80 bpm) or tidal volume (1 mL/100 g body weight). Body temperature was measured continuously via rectal probe (CWE, Inc., Ardmore, PA, USA) and maintained at 37 ± 0.5°C by a water‐circulating blanket. Catheters were inserted into the brachial artery and jugular vein to record ABP and continuously infuse fluids (0.75% NaCl and 0.25% glucose 0.5 mL/h), respectively. Through a retroperitoneal incision the right or left kidney was gently retracted. A heat‐stretched Micro‐Renathane catheter (0.037′×0.023′, Braintree Scientific, Braintree, MA, USA) was inserted into the ureter and advanced to the exit of the renal pelvis. Continuous urine flow throughout the experiment confirmed proper placement. Then the right or left renal nerve (see the experimental protocols that follow) was isolated, placed on bipolar stainless‐steel electrode and insulated with KWIK‐SIL (World Precision Instruments, Sarasota, FL, USA). Nerve signals were amplified (50,000×), filtered (0.3–1.0 kHz, AM Systems, Sequim, WA, USA), digitized (2 kHz), rectified and integrated (0.5 s time constant) using a Micro1401 and Spike 2 software. ARNA signals were calculated by subtracting noise obtained at the end of experiments by cutting the nerve between the kidney and electrode. ARNA was expressed as a percentage of baseline values normalized to 100%. After all surgical procedures were completed, isoflurane anaesthesia was replaced by Inactin (120 mg/kg, IV). Then the animals were ventilated with room air. The plane of anaesthesia was monitored throughout the experiment by the absence of a withdrawal reflex or pressor response (<5 mmHg) to foot pinch. Animals stabilized for 60 min before recordings, and experimental protocols began.

Experiment 1 – ARNA responses to renal artery occlusion

WT and Trpv1−/− littermates were prepared as described earlier. In addition, a 3‐0 silk suture was placed around the right renal artery. Renal artery blood flow was measured using a Transonic T5420 probe placed distal to the silk ligature. Then the right renal nerve was isolated adjacent to the kidney. After variables stabilized for 60 min, ARNA was isolated from sympathetic efferent nerve activity by sectioning the nerve proximal to the electrode (between the electrode and aorta). At least 15 min later graded reductions in renal blood flow (25%, 50%, 75%, 100% of baseline renal blood flow) were performed for 90 s by raising the silk suture using a stereotaxic arm. The height was adjusted to maintain renal blood flow at the selected level. Each reduction was tested once in a randomized order with at least 5 min between trials to allow renal blood flow to return to baseline levels for a minimum of 2 min. Data were averaged into 10‐s bins. Baseline responses (30 s) were compared to the ARNA response over two different phases (phase 1: 10–30 s vs. phase 2: 60–80 s).

Experiment 2 – Elevated renal pelvic pressure

After renal artery occlusion was performed on the right kidney, the left kidney was gently retracted. The left renal pelvis was catheterized, and the left renal nerve was isolated as described earlier. After ARNA was isolated, variables were monitored for an additional 15 min before experiments began. Renal pelvic pressure steps were performed by connecting the renal pelvic catheter to a pressure transducer and water column. The water column was increased manually to pre‐calibrated levels (0, 5, 10 or 20 mmHg for 60 s) in a randomized order with at least 2 min between trials. Data were averaged into 10‐s bins. Baseline responses (30 s) were compared to the average response (60 s) over the entire pressure step.

Experiment 3 – Effect of intrapelvic capsazepine on ARNA response to elevated renal pelvic pressure in WT and Trpv1−/− rats

The contribution of TRPV1 channels to ARNA responses during elevated renal pelvic pressure is based upon pharmacological blockade of TRPV1 channels using capsazepine. To assess whether these effects are attributed to TRPV1 or a non‐specific action of the drug, a final set of experiments infused capsazepine into the renal pelvis of WT and Trpv1−/− rats during ARNA recordings and renal pelvic pressure steps. A separate group of WT and Trpv1−/− rats were prepared as described earlier. The left kidney was gently retracted. A heat‐stretched Micro‐Renathane catheter (0.037′×0.023′, Braintree Scientific) was inserted into the ureter and advanced to the exit of the renal pelvis to collect urine and increase renal pelvic pressure. Intrapelvic infusion of drugs was performed using a second catheter (PE‐10) inserted alongside the first ureteral catheter but advanced 0.5 cm further to place the tip inside the renal pelvis. The ureter incision was sealed by a few drops of KWIK‐CAST (World Precision Instruments). Then the left renal nerve was isolated and placed on bipolar electrodes as described earlier. After animals stabilized for 60 min, the ARNA signal was isolated by cutting the nerve proximally. A saline vehicle (10 mM phosphate buffer, 150 mM NaCl, 25 mM KCl, pH 6.5) was continuously infused at a rate of 50 µL/min through the PE‐10 renal pelvic catheter. ARNA responses to intrapelvic infusion of capsaicin (3 µM, 50 µL) or increased pelvic pressure (10 and 20 mmHg, 60 s) were tested during the intrapelvic infusion (50 µL/min) of saline vehicle, capsazepine (50 µM dissolved in saline vehicle), or saline vehicle ‘washout’. Trpv1−/− rats also received an infusion of bradykinin (10 µM, 50 µL) at the beginning of the experiments to test the placement of the catheter and viability of the ARNA recording. Each solution was infused for a minimum of 20 min before the stimuli were tested. Each animal received all three infusions in the order stated earlier. The concentration of capsazepine was based on the average concentration used in prior studies in which the drug attenuated ARNA responses (Feng et al., 2008; Zhu et al., 2007). Data were averaged into 10‐s bins. Baseline responses (30 s) were compared to the ARNA response (60 s) over the entire renal pelvic pressure step. ARNA responses to renal pelvic capsaicin or bradykinin were compared between baseline values (30 s) and the 30‐s peak response.

Data analysis

Data are presented as mean ± SD plus individual data points for male and female rats. Data were analysed (Systat 10.2) using a three‐way ANOVA (strain, sex, time; renal artery occlusion), two‐way ANOVA (strain, sex; partial reduction in renal blood flow), two‐way ANOVA (strain, sex; experiment 2) or one‐way repeated‐measures ANOVA (treatment, experiment 3). Because there were no sex differences in any variable across experiments (see Results), data were combined but individual data points for males versus females are illustrated. When significant F values were obtained, an independent or paired t test with a layered Bonferroni correction was performed. If a data set failed normality, a Mann–Whitney U test was performed. In all instances the statistical conclusions were similar between the non‐parametric and parametric tests. Linear regression analysis was performed between ARNA and renal pelvic pressure for each rat and averaged within a strain (Sigma Plot 16). Group sizes are noted in the text and figure legends.

An inclusion/exclusion criterion for nerve recordings was a minimum signal‐to‐noise ratio of 3:1 of the whole renal nerve recording (before the nerve was sectioned to isolate ARNA). Only one WT rat did not meet this criterion for the renal pelvic pressure experiments.

Results

Experiment 1 – ARNA responses to renal artery occlusion or ischaemia

Baseline haemodynamics were recorded from a 15‐min period before any experimental protocols began. A two‐way ANOVA revealed no significant differences in baseline parameters between WT and Trpv1−/− strains for mean ABP (122 ± 15 vs. 129 ± 10 mmHg; strain P = 0.316, sex P = 0.318, interaction P = 0.176), heart rate (379 ± 30 vs. 402 ± 24 bpm; strain P = 0.118, sex P = 0.674, interaction P = 0.930) or ARNA (0.35 ± 0.24 vs. 0.34 ± 0.21 µV; strain P = 0.427, sex P = 0.255, interaction P = 0.912). Although baseline renal blood flow did not differ between strains (5.1 ± 1.4 vs. 4.5 ± 1.3 mL/min, strain P = 0.332), renal blood flow was lower in female versus male rats independent of strain (4.2 ± 0.9 vs. 5.6 ± 1.5mL/min; sex P = 0.026, interaction P = 0.881).

An initial set of experiments tested the extent to which TRPV1 channels contribute to ARNA responses during renal artery occlusion (100% blood flow reduction). In WT rats renal artery occlusion produced a biphasic ARNA response. Phase 1 was characterized by an initial increase at the onset of occlusion that persisted over the next 45 s. Phase 2 began at ∼45 s and was reflected by a substantial increase in ARNA that lasted for the remainder of the occlusion (Fig. 1A ). In Trpv1−/− rats total renal artery occlusion initially increased ARNA (phase 1); however the ARNA response during phase 2 was significantly blunted or absent (Fig. 1B ). Summary data for baseline, phase 1 and phase 2 are presented in Fig 1C . A three‐way ANOVA (strain, sex, time) of ARNA revealed a significant main effect for strain (P < 0.001) and time (P < 0.001) but not sex (P = 0.304). Renal artery occlusion significantly increased ARNA of both WT and Trpv1−/− rats in phases 1 and 2 (Fig. 1C ). However the ARNA response in phase 2, but not phase 1, was significantly attenuated in Trpv1−/− rats. As expected total renal artery occlusion produced significant but similar decreases in absolute renal blood flow (ANOVA: strain P = 0.385, sex P = 0.152, time P < 0.001) or renal blood flow as percentage baseline (ANOVA: strain P = 0.513, sex P = 0.849, time P < 0.001). Total renal artery occlusion also increased mean ABP (ANOVA: strain P = 0.0473, sex P = 0.214, time P < 0.001). WT rats displayed a significant pressor response during phase 1 (P = 0.150) and phase 2 (P < 0.001). Mean ABP did not significantly increase in Trpv1−/− rats (P = 0.130). In fact the pressor response in phase 2 was significantly attenuated in Trpv1−/− versus WT rats (Fig. 1C ). Heart rate did not change in either group (data not shown).

Figure 1. ARNA (afferent renal nerve activity) responses to total renal artery occlusion.

Figure 1

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A & B, arterial blood pressure (ABP, mean ABP = grey line), renal blood flow (RBF, mean RBF = grey line) and integrated and rectified ARNA during total renal artery occlusion (90 s) in wild‐type (WT) and Trpv1−/– rats. Total renal artery occlusion produced a biphasic response in ARNA associated with an initial increase (phase 1) followed by a substantial increase after ∼45 s (phase 2). Phase 2 was largely attenuated in Trpv1−/– rats. Examples (0.4 s) of original ARNA are illustrated at baseline, phase 1 and phase 2. C, mean ± SD of ARNA, RBF and change in mean ABP of WT (n = 7M, 5F) and Trpv1−/– (n = 5M, 5F) rats during total renal artery occlusion. Individual data points for males versus females are represented by Χ versus Ο. Phase 2 but not phase 1 was largely attenuated in Trpv1−/– rats. *P < 0.001 versus baseline within same group.

ARNA responses to graded reductions in renal blood flow (75%, 50% and 25% of baseline) were also tested in both strains. Partial reductions in renal blood flow increased ARNA in both WT and Trpv1−/− rats (Fig 2A and  B ). The ARNA response began at the onset of blood flow reduction and persisted for the 90‐s manipulation. In marked contrast to total artery occlusion, these ARNA responses did not exhibit a biphasic response in either strain. Therefore summary data represent a 90‐s average and are presented in Fig. 2C . Although a reduction in renal blood flow significantly increased ARNA from baseline values within WT (75%: P = 0.012, 50%: P < 0.001, 25%: P < 0.001) and Trpv1−/− rats (75%: P = 0.024, 50%: P < 0.001, 25%: P < 0.001), a two‐way ANOVA at each renal blood flow level revealed no significant differences in ARNA between strains (Fig. 2C ). Partial reductions in renal blood flow at 50% and 25% increased mean ABP of WT (75%: P = 0.330, 50%: P < 0.016, 25%: P < 0.001) but not Trpv1−/− rats (ANOVA P = 0.348). In fact, a two‐way ANOVA revealed that the change in mean ABP at 50% and 25% renal blood flow was significantly attenuated in Trpv1−/− versus WT rats (Fig. 2C ). Heart rate did not change in either group (data not shown).

Figure 2. ARNA (afferent renal nerve activity) responses to graded reductions in renal arterial blood flow.

Figure 2

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A and B, ABP (arterial blood pressure), RBF (renal blood flow) and integrated/rectified ARNA in response to partial reductions in renal blood flow (25%, 50%, 75%) produced graded increases in ARNA of both WT (wild‐type) and Trpv1−/− rats. ARNA examples (0.5 s) at baseline (a) and during renal blood flow reduction (b) are illustrated. C, mean ± SD of ARNA, RBF (absolute and % baseline) and change in mean ABP of WT (n = 7M, 5F) and Trpv1−/− (n = 5M, 5F) rats at 100%, 75%, 50% and 25% RBF. Values represent a 90‐s average during the reduction in RBF. Individual data points for males versus females are represented by Χ versus Ο. P‐values from two‐way ANOVA are inserted above each figure.

A linear regression analysis between ARNA and renal blood flow (% baseline) was performed for each animal and then average per group. The average slope between ARNA and renal blood flow did not differ between WT and Trpv1−/− rats (−0.68 ± 0.35 vs. −0.83 ± 0.42, strain P = 0.395, sex P = 0.873, interaction P = 0.168). The average Pearson's r value did not differ between WT and Trpv1−/− rats (0.77 ± 0.16 vs. 0.79 ± 0.23, strain P = 0.776, sex P = 0.345, interaction P = 0.399).

Experiment 2 – ARNA responses to elevated renal pelvic pressure

A second major aim of this study was to test the contribution of TRPV1 channels to ARNA responses during changes in renal pelvic pressure. These manipulations were performed in rats from experiment 1, but the recordings and manipulations were performed in the contralateral or left kidney. One male WT rat was excluded due to a low signal‐to‐noise ratio in the whole renal nerve recording (<3:1). A two‐way ANOVA revealed small but significant differences in baseline parameters between WT and Trpv1−/− strains for mean ABP (104 ± 11 vs. 116 ± 5 mmHg, strain P = 0.009, sex P = 0.782, interaction P = 0.733), heart rate (366 ± 32 vs. 400 ± 30 bpm, strain P = 0.019, sex P = 0.806, interaction P = 0.301) but not ARNA (0.49 ± 0.25 vs. 0.47 ± 0.35 µV, strain P = 0.577, sex P = 0.947, interaction P = 0.388). In WT rats elevated renal pelvic pressure produced a complex ARNA response characterized by an initial peak at the onset of the pressure step followed by a plateau phase. ARNA returned to baseline values as the pressure step ended (Fig. 3A ). The ARNA responses were largely graded or pressure dependent. Surprisingly elevated renal pelvic pressure also increased ARNA of Trpv1−/− rats (Fig. 3B ).

Figure 3. ARNA (afferent renal nerve activity) responses to graded increases in renal pelvic pressure.

Figure 3

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Arterial blood pressure (ABP, mean ABP = grey line), renal pelvic pressure and integrated/rectified ARNA during increased pelvic pressure (5, 10 and 20 mmHg, 60 s) in wild‐type (A) and Trpv1−/−(B) rats. Increased pelvic pressure produced pressure‐dependent increases in ARNA that did not differ between strains. Examples (0.2 s) of original ARNA are illustrated at baseline and during the pressure step. Mean ± SD are presented in Fig. 4.

Summary data using a 60‐s average of ARNA, pelvic pressure and mean ABP of both WT and Trpv1−/− rats are shown in Fig. 4. A two‐way ANOVA performed at each pressure step (0, 5, 10 and 20 mmHg) revealed no significant differences in ARNA, pelvic pressure and the change in mean ABP between WT and Trpv1−/− rats. In addition there were no sex differences in any variable (Fig. 4). In addition ARNA responses were plotted as a function of pelvic pressure for both WT and Trpv1−/− rats (Fig. 4). A linear regression of ARNA versus renal pelvic pressure was performed for each animal and then averaged within a strain. The average Pearson's r value was not different between WT and Trpv1−/− rats (0.86 ± 0.16 vs. 0.82 ± 0.14, strain P = 0.661, sex P = 0.372, interaction P = 0.974). The average slope between ARNA and pelvic pressure also did not differ between WT and Trpv1−/− rats (Fig. 5C ).

Figure 4. Summary of ARNA (afferent renal nerve activity) responses to increased renal pelvic pressure.

Figure 4

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Mean ± SD of ARNA, pelvic pressure and change in mean ABP (arterial blood pressure) of WT (wild‐type, n = 6M, 5F) and Trpv1−/− (n = 5M, 5F) rats during increased 60‐s renal pelvic pressure steps (0, 5, 10, 20 mmHg). Individual data points for males versus females are represented by Χ versus Ο. Elevated renal pelvic pressure increased ARNA, but these responses did not differ between WT and Trpv1−/− rats. Two‐way ANOVA revealed no differences in any variable for both sex and strain.

Figure 5. ARNA (afferent renal nerve activity) as a function of renal pelvic pressure.

Figure 5

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A and B, scatter plot of ARNA as a function of pelvic pressure for WT (wild‐type, n = 6M, 5F) and Trpv1−/− (n = 5M, 5F) rats. C, a linear regression analysis of each animal was performed and then averaged within each strain. An ANOVA revealed no significant difference in the slopes between WT and Trpv1−/– rats (strain P = 0.303, sex P = 0.0715, interaction P = 0.688). Individual data points for males versus females are represented by Χ versus Ο.

Experiment 3 – intrapelvic capsazepine attenuates ARNA responses to renal pelvic pressure in WT and Trpv1−/− rats

Prior studies reported that intrapelvic infusion of capsazepine attenuated ARNA responses to renal pelvic pressure. Because ARNA responses to renal pelvic pressure were not different between WT and Trpv1−/− rats, a final set of experiments tested whether the effects of capsazepine were attributed to antagonism of the TRPV1 channel. There were no differences between WT and Trpv1−/− rats for baseline mean ABP (100 ± 8 vs. 105 ± 3 mmHg, P = 0.342), heart rate (368 ± 26 vs. 394 ± 60 bpm, P = 0.457) or ARNA (0.46 ± 0.22 vs. 0.41 ± 0.10 µV, P = 0.745). In WT rats a 20 mmHg increase in renal pelvic pressure elevated ARNA (Fig. 6A ). As expected intrapelvic infusion of capsazepine blunted the ARNA response to a 20 mmHg pressure step. After a 20‐min saline ‘washout’, the ARNA response returned. ARNA responses to intrapelvic infusion of capsaicin (3 µM) were eliminated by capsazepine (saline: 233 ± 59% vs. capsazepine: 93 ± 7%, n = 4, P < 0.001) but returned after a saline ‘washout’ (saline: 233 ± 59% vs. washout: 184 ± 37%, n = 4, P = 0.083). When the same manipulation was performed in Trpv1−/– rats, a 20 mmHg elevation in renal pelvic pressure increased ARNA. However intrapelvic infusion of capsazepine also blunted the ARNA response in Trpv1−/− rats. The ARNA response subsequently returned after a 20‐min saline ‘washout’. Intrapelvic infusion of capsaicin did not evoke an ARNA response in Trpv1−/− rats (98 ± 1%, P = 0.464), but intrapelvic infusion of bradykinin increased ARNA (199 ± 13%, P < 0.00295). Summary data are presented in Fig. 6B and illustrate that intrapelvic infusion of capsazepine blunted ARNA responses to 10 and 20 mmHg renal pelvic pressure in both WT and Trpv1−/− rats. No analyses of sex differences were performed due to insufficient number of males versus females.

Figure 6. ARNA (afferent renal nerve activity) responses to renal pelvic pressure before, during or after intrapelvic infusion of capsazepine.

Figure 6

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ABP (arterial blood pressure, mean ABP = grey line), renal pelvic pressure and integrated/rectified ARNA during intrapelvic infusion of capsaicin (3 µM, 50 µL) or increased pelvic pressure (20 mmHg, 60 s) after a 20‐min intrapelvic infusion of saline, capsazepine (100 µM) or saline washout. A, in WT (wild type) rats capsazepine attenuated ARNA responses to renal pelvic pressure and eliminated responses to capsaicin. B, in Trpv1−/− rats (1M, 2F), capsazepine again attenuated ARNA responses to renal pelvic pressure. Summary data represented as mean ± SD and individual data points (male x, female O) are presented on the right. *P<0.001 versus saline treatment.

Discussion

TRPV1 channels are widely expressed in renal sensory neurons and postulated to play a pivotal role in ARNA responses to mechano‐ and chemosensitive stimuli. The present study tested the contribution of TRPV1 channels to ARNA activation during renal artery occlusion, renal ischaemia and elevated renal pelvic pressure using a recently developed Trpv1−/− rat. First, we demonstrated that ARNA responses to prolonged renal artery occlusion were significantly attenuated in Trpv1−/− versus WT rats. Second, ARNA responses to partial reductions in renal artery blood flow were not different between strains. Third, ARNA responses to elevated renal pelvic pressure were surprisingly not different between WT and Trpv1−/− rats. Collectively these findings suggest TRPV1 channels play distinct roles in renal interoception and ARNA activation, which include chemosensitive stimuli during prolonged renal artery occlusion but not mechanosensitive stimuli during increased renal pelvic pressure or acute reduction in renal blood flow.

In the present study renal artery occlusion produced a biphasic ARNA response characterized by an initial increase in ARNA at the onset of occlusion followed by a delayed but substantial increase in ARNA after ∼45 s. This response profile may reflect the presence of two distinct populations of renal sensory neurons. For example single‐unit recordings of renal sensory afferents revealed the presence of two populations: (1) R1 renal chemoreceptor units activated by prolonged renal artery or venous occlusion and asphyxia but not ureteral pressure (Recordati et al., 1978), and (2) R2 chemoreceptor units responsive to urine composition and abrupt changes in renal blood flow (Recordati et al., 1980). Thus R2 chemoreceptor units may contribute to phase 1 (initial 0–30 s), whereas R1 chemoreceptor units may contribute to phase 2 (45–90 s). Interestingly the ARNA response in phase 2 was significantly attenuated in Trpv1−/− rats. TRPV1 channels are responsive to mechanosensitive stimuli, temperature, pH and various chemical factors (Julius, 2013; Nilius, 2007; Rosenbaum & Simon, 2007). The ARNA activation during prolonged renal occlusion during phase 2 may be triggered by local changes in pH or release of chemical factors to activate TRPV1 and increase ARNA. Currently there are limited data regarding the extent to which renal sensory afferents respond to pH or ischaemia‐related metabolic factors.

ARNA abruptly increased at the onset of renal artery occlusion or renal ischaemia in a flow‐dependent manner. In fact, ARNA was directly correlated with the reduction in renal blood flow. The time course and flow dependency of these responses suggest that a renal baroreceptor or mechanoreceptor may mediate this response. The abrupt onset of the ARNA response mirrors single‐unit recordings of R2 chemoreceptor units (Recordati et al., 1980). These units responded promptly to renal artery occlusion and backflow of urine. Partial or graded reductions in renal blood flow were not tested in this study. However, an intra‐arterial infusion of saline during renal artery occlusion attenuated the discharge response of these units. Whether this is attributed to a ‘wash‐out’ effect of a metabolite versus mechanoreceptor stimulus remains unclear. The term ‘R2 chemoreceptor’ originated from observations that these sensory fibres responded to the chemical composition of urine rather than pressure (Recordati et al., 1980). However a mechanoreceptor mechanism cannot be ruled out for afferent responses to renal artery clamping due to the abrupt and immediate onset of the response. The current experiments did not test whether the ARNA activation at the onset of ischaemia can be directly attributed to changes in flow versus pressure. Regardless, deletion of TRPV1 did not affect these responses nor the relationship between ARNA and renal blood flow. Altogether these findings suggest that TRPV1 channels mediate different phases of ARNA activation during renal artery occlusion, and a separate and distinct neural mechanism senses changes in flow or pressure.

Renal artery stenosis or occlusion produces a pressor response through neurogenically mediated increases in vascular resistance and activation of the renin–angiotensin system (Faber & Brody, 1983). The neurogenic component was eliminated after denervation of the stenotic kidney (Faber & Brody, 1985). In the current experiments renal artery occlusion or large reductions in renal blood flow produced a pressor response in WT rats but not in Trpv1−/− rats. The attenuated pressor effect may be attributed to the TRPV1‐dependent activation of renal sensory nerves, sympathetic outflow and renin–angiotensin system, or to TRPV1‐dependent regulation of myogenic tone (Phan et al., 2022).

Increased renal pelvic pressure has been postulated to elevate ARNA through the release of a TRPV1‐mediated substance P (Ditting et al., 2012; Feng et al., 2008; Kopp & Smith, 1991, 1993). The role of TRPV1 channels has been exclusively based on the observation that intrapelvic infusion of capsazepine attenuated ARNA responses to renal pelvic pressure (Ditting et al., 2012; Feng et al., 2008). However capsazepine is a non‐specific TRPV1 antagonist that also interferes with numerous other targets (Behrendt et al., 2004; Bevan et al., 1992; Docherty et al., 1997; Kistner et al., 2016; Liu & Simon, 1997; Yamamura et al., 2004). Therefore, we re‐evaluated the contribution of the TRPV1 channel and demonstrated that ARNA responses to 5, 10 and 20 mmHg renal pelvic pressure were not different between WT and Trpv1−/− rats. In fact, when ARNA was plotted as a function of pelvic pressure, the slopes between WT and Trpv1−/− rats were similar. Moreover intrapelvic infusion of capsazepine attenuated ARNA response to renal pelvic pressure in both WT and Trpv1−/− rats, thereby suggesting a non‐TRPV1 mechanism of action. These new findings suggest ARNA activation during increased renal pelvic pressure is not mediated by TRPV1 channels.

Renal sensory nerves innervate the vasculature, renal tubules, glomeruli and pelvic wall (Ferguson & Bell, 1988; Ferguson et al., 1988; Kopp, 2015; Marfurt & Echtenkamp, 1991; Osborn et al., 2021). Our findings indicate that TRPV1 channels contribute to ARNA activation during prolonged renal artery occlusion but not mechanosensitive stimuli such as acute reductions in renal artery flow or elevated pelvic pressure. TRPV1 fibres innervate the renal pelvic wall, but recent reports also suggest that TRPV1 fibres innervate both the glomeruli and vasculature in the mouse (N'Guetta et al., 2024; Tyshynsky et al., 2023). In these studies TRPV1 fibres were visualized through a cross between TRPV1Cre and TdTomato‐reporter (Ai14 or R26) mouse strains. TRPV1 is widely expressed in sensory neurons during development but decreases significantly by adulthood (Cavanaugh, Chesler, Braz et al., 2011; Cavanaugh, Chesler, Jackson et al., 2011). Thus, a portion of the TRPV1 fibres in these studies may not be TRPV1 due to the cell‐lineage and developmental expression of TRPV1 and hence TdTomato. In fact our preliminary data suggest approximately 60% of renal sensory neurons are TRPV1 positive in the adult mouse. In the adult rat, the majority (∼85%–90%) of renal sensory neurons are TRPV1 positive (Stocker & Sullivan, 2023), yet the present findings suggest that TRPV1 channels do not mediate ARNA activation to mechanosensitive stimuli such as acute reduction in renal blood flow or elevated renal pelvic pressure. The molecular identity of a renal mechanosensor is unknown. Recently PIEZO2‐positive fibres were reported to innervate the vasculature in the embryonic mouse and adult human kidney (N'Guetta et al., 2024). Subsequent experiments using retrograde tracers identified the presence of PIEZO2‐positive mouse renal sensory neurons. Although these observations are promising, caution should be exercised when interpreting these findings as the injection volumes of tracers into the kidney were excessively large (3–5µL per injection) and produced labelling in the contralateral DRG, thereby suggesting leak and non‐specificity. Clearly future experiments are needed to identify the role of PIEZO2 channels or other potential mechanosensitive channels to ARNA activation during changes in blood flow or pelvic pressure.

In summary the new findings suggest TRPV1 channels play distinct roles in renal interoception and ARNA activation, which include chemosensitive but not mechanosensitive stimuli. These findings suggest TRPV1 may play a pivotal role in haemodynamic and homeostatic responses to renal artery stenosis or acute kidney injury produced by severely compromised blood flow. In regard to the former we recently reported that Trpv1−/− rats exhibited attenuated hypertension, lower ARNA and improved kidney function after renovascular hypertension produced by unilateral renal stenosis (Stocker & Sullivan, 2023). In regard to the latter activation of TRPV1 via systemic capsaicin protects against renal ischaemia‐reperfusion injury in mice (Chen et al., 2014), but kidney function and indices of renal damage are not different between WT and Trpv1−/− mice. There may be species differences as the proportion of TRPV1‐expressing neurons differs between mice and rats (unpublished observations). In rats renal nerve denervation protected against ischaemic reperfusion injury (Kim & Padanilam, 2015), and chemical ablation of TRPV1‐expressing afferents reduced renal efferent sympathetic activation in response to a 60‐min renal artery occlusion (Marreiros et al., 2025). Future studies are needed to elucidate renal afferent responses to extended renal artery occlusion analogous to ischaemia‐reperfusion injury models and also assess the contribution of TRPV1 channel activation.

Additional information

Competing interests

The authors declare no competing interests.

Author contributions

S.D.S. and L.J.D. conceived and designed the research work; S.D.S. and J.B.S. performed the experiments; J.B.S. and S.D.S. analysed data; S.D.S., J.B.S. and L.J.D. interpreted the results of the experiments; S.D.S. prepared the figures and drafted the manuscript; and J.B.S., L.J.D. and S.D.S. edited and revised the manuscript. All authors have read and approved the final version of the manuscript and agree to be accountable for all aspects of the work ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

Funding

This work was supported by NIH Grants R01 HL152680 (S.D.S.), R01 DK135541 (S.D.S.), R01 HL163906 (S.D.S.) and K99 DK133561 (L.J.D.).

Supporting information

Peer Review History

TJP-604-1415-s001.pdf (480.5KB, pdf)

Acknowledgements

The authors have nothing to report.

Biography

Jacob B. Sullivan studied neuroscience at the University of Pittsburgh. As an undergraduate student, he investigated the role of TRPV1 channels in renovascular hypertension. Then, he continued to explore how TRPV1 channels are involved in renal interoception and renal sensory nerve function. Following graduation, he has continued to work in the Stocker Lab.

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Handling Editors: Vaughan Macefield & Diana Martinez

The peer review history is available in the Supporting Information section of this article (https://doi.org/10.1113/JP289721#support‐information‐section).

Data availability statement

The data that support these findings of this study are available from the corresponding authors upon reasonable request.

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Associated Data

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Supplementary Materials

Peer Review History

TJP-604-1415-s001.pdf (480.5KB, pdf)

Data Availability Statement

The data that support these findings of this study are available from the corresponding authors upon reasonable request.

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