Deletion of the Transient Receptor Potential Vanilloid-1 (TRPV1) in Rats Attenuates Renal Sensory Nerve Responses to Renal Ischemia

Renal sensory nerves innervate the pelvic wall, tubules, glomeruli and vasculature and respond to renal ischemia, elevated pelvic pressure and various chemokines. The transient receptor potential vanilloid-1 (TRPV1) channel is widely expressed in sensory neurons and detects noxious and mechanical stimuli, pH, and chemokines. We hypothesized that the TRPV1 channel contributes to elevated afferent renal nerve activity (ARNA) during renal ischemia or elevated renal pelvic pressure. To test this hypothesis, a Trpv1 -/- rat was generated by CRISP/Cas9 and 26-bp deletion in exon 3. First, the TRPV1 agonist capsaicin (300 nM) evoked a Ca++ transient in 57.6% of dissociated dorsal root ganglion neurons from wild-type (WT) rats (224 neurons / 4 rats) but only 2.5% of neurons in Trpv1 -/- rats (395 neurons / 3 rats). Second, renal artery occlusion (90s) ceased renal blood flow (WT: 5.2±0.3 to 0.1ml/min vs Trpv1 -/- : 4.6±0.4 to 0.1±0.1mL/min) and significantly increased ARNA in both strains. However, ARNA was significantly attenuated in Trpv1 -/- versus WT rats (325±43% vs 490±68%, n=10; p<0.05). The pressor response to renal artery occlusion was also significantly attenuated in Trpv1 -/- versus WT rats (0±1mmHg vs 5±1mmHg, p<0.05). In marked contrast, elevated renal pelvic pressure (60s) produced similar increases in ARNA between Trpv1-/- versus WT rats at 10mmHg (164±12% vs 156±7%, n=10) or 20 mmHg (195±13% vs 219±23%, n=10). Finally, RNAscope and novel transgenic reporter rats were used to assess the neurochemical phenotype of renal sensory neurons retrogradely-labeled with cholera toxin subunit B-Alexa Fluor647 (2mg/mL, 3 injections, 1uL each). The majority of rat renal sensory neurons were TRPV1-positive as revealed by RNAscope (97±1%, n=4) or a novel TRPV1-cre-TdTomato reporter rat (96±1%, n=4). In addition, these neurons expressed the vesicular glutamate transporter-2 (Vglut2) as revealed by RNAscope (96±1%, n=4) or a novel Vglut2-cre-TdTomato reporter rat (90±2 %, n=4). Lastly, these neurons were peptidergic and expressed Tac1 (90±2%, n=4) and CGRP (90±1%, n=4) but few expressed neurofilament-200 (8±1%, n=4). Altogether, the majority of rat renal sensory neurons are glutamatergic and peptidergic TRPV1-positive neurons. The TRPV1 channel contributes to renal afferent activation during renal ischemia but not elevated pelvic pressure. NIH R01 HL152680 and DK135541 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.