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. 2023 Aug;80(8):1671-1682.
doi: 10.1161/HYPERTENSIONAHA.123.21153. Epub 2023 Jun 19.

Deletion of the Transient Receptor Potential Vanilloid 1 Channel Attenuates Sympathoexcitation and Hypertension and Improves Glomerular Filtration Rate in 2-Kidney-1-Clip Rats

Sean D Stocker  1 , Jacob B Sullivan  1
Affiliations

Deletion of the Transient Receptor Potential Vanilloid 1 Channel Attenuates Sympathoexcitation and Hypertension and Improves Glomerular Filtration Rate in 2-Kidney-1-Clip Rats

Sean D Stocker et al. Hypertension. 2023 Aug.

Abstract

Background: Renal denervation lowers arterial blood pressure in both clinical populations and multiple experimental models of hypertension. This therapeutic effect is partly attributed to the removal of overactive renal sensory nerves. The TRPV1 (transient receptor potential vanilloid 1) channel is highly expressed in renal sensory nerves and detects changes in noxious and mechanosensitive stimuli, pH, and chemokines. However, the extent to which TRPV1 channels contribute to 2-kidney-1-clip (2K1C) renovascular hypertension has not been tested.

Methods: We generated a novel Trpv1-/- (TRPV1 knockout) rat using CRISPR/Cas9 and 26-bp deletion in exon 3 and induced 2K1C hypertension.

Results: The majority (85%) of rat renal sensory neurons retrogradely labeled from the kidney were TRPV1-positive. Trpv1-/- rats lacked TRPV1 immunofluorescence in the dorsal root ganglia, had a delayed tail-flick response to hot but not cold water, and lacked an afferent renal nerve activity response to intrarenal infusion of the TRPV1 agonist capsaicin. Interestingly, 2K1C hypertension was significantly attenuated in male Trpv1-/- versus wild-type rats. 2K1C hypertension significantly increased the depressor response to ganglionic blockade, total renal nerve activity (efferent and afferent), and afferent renal nerve activity in wild-type rats, but these responses were attenuated in male Trpv1-/- rats. 2K1C hypertension was attenuated in female rats with no differences between female strains. Finally, glomerular filtration rate was reduced by 2K1C in wild-type rats but improved in Trpv1-/- rats.

Conclusions: These findings suggest that renovascular hypertension requires activation of the TRPV1 channel to elevate renal afferent and sympathetic nerve activity, reduce glomerular filtration rate, and increase arterial blood pressure.

Keywords: autonomic nervous system; blood pressure; glomerular filtration rate; hypertension; kidney.

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Conflict of interest statement

Disclosures None.

Figures

Figure 1.
Figure 1.. Quantification of Rat Renal Sensory Neurons Expressing Transient Receptor Potential Vanilliod 1 (TRPV1)
A, Number of retrogradely labelled neurons in the dorsal root ganglion at each thoracic and lumbar spinal segment in both control and 2-kidney-1-clip (2K1C) rats. B, The percentage of retrogradely labelled neurons that were Trpv1, IB4, or Trpv1 plus IB4 positive. C, Low power image of rat dorsal root ganglia processed for Cholera Toxin Subunit B (CTB-647, blue), TRPV1 (red), and IB4 (green). D-F, Inset images of CTB-647 (blue), Trpv1 (red), and IB4 (green). There were no differences in the number of neurons and proportion expressing Trpv1 versus IB4 between male vs female or sham versus 2K1C.
Figure 2.
Figure 2.. Validation of Transient Receptor Potential Vanilloid 1 Knockout (Trpv1−/−) Rats
A, TRPV1 (RED) and IB4 (green) immunofluorescence of the DRG in wild-type and Trpv1−/− rat. Note, the absence of TRPV1 signal in the DRG of the Trpv1−/− rat. B, Number of eye-wipes to one drop of capsaicin (100uM) was absent in Trpv1−/− versus wild-type rats. C, Tail-flick latency was significantly delayed to hot (50°C) but not cold (0°C) water in Trpv1−/− versus wild-type rats. D, (TOP) Intrarenal artery infusion of capsaicin increased fferent renal nerve activity (ARNA) in wild-type but not Trpv1−/− rats. (BOTTOM) Intrarenal artery infusion of bradykinin increased ARNA in both wild-type and Trpv1−/− rats. Summary data presented as mean±SEM and individual data points are presented on the right. *P<0.05 Wild-type versus Trpv1−/− ; #P<0.05 vs saline or 0µM
Figure 3.
Figure 3.. Hemodynamic responses to 2-kidney-1-Clip (2K1C) Hypertension in Wild-Type and Transient Receptor Potential Vanilloid 1 Knockout (Trpv1−/−) Male Rats
A, Mean±SEM of mean, systolic, and diastolic ABP as well as pulse pressure and heart rate in male wild-type and Trpv1−/− rats. Values were averaged between day and night periods. B, Mean±SEM and individual data points of the depressor response to ganglionic blockade with hexamethonium (30mg/kg, ip) on Day 0 and 28. C, Mean±SEM and individual data points of kidney mass for both clipped and unclipped kidneys in wild-type and Trpv1−/− rats. *P<0.05 wild-type vs Trpv1−/−, #P<0.05 unclipped vs clipped.
Figure 4.
Figure 4.. Hemodynamic Responses to 2-Kidney-1-Clip (2K1C) Hypertension in Wild-Type and Transient Receptor Potential Vanilloid 1 Knockout (Trpv1−/−) Female Rats
A, Mean±SEM of mean, systolic, and diastolic ABP as well as pulse pressure and heart rate in female wild-type and Trpv1−/− rats. Values were averaged between day and night periods. B, Mean±SEM and individual data points of the depressor response to ganglionic blockade with hexamethonium (30mg/kg, ip) on Day 0 and 28. C, Mean±SEM and individual data points of kidney mass for both clipped and unclipped kidneys in wild-type and Trpv1−/− rats. Note, there were no statistical differences between genotypes of female rats for any reported variable.
Figure 5.
Figure 5.. Mean Arterial Blood Pressure (ABP), Renal Sympathetic Nerve Activity (SNA) and Afferent Renal Nerve Activity (ARNA) in Male Wild-Type and Transient Receptor Potential Vanilloid 1 Knockout (Trpv1−/−) Rats
A, Examples (1 s) of arterial blood pressure (ABP) and RSNA for male wild-type and Trpv1−/− rats between Day 21-28 after sham or 2-kidney-1-clip (2K1C) surgery. B, Example (1s) of ARNA for male wild-type and Trpv1−/− rats between Day 21–28 after sham or 2K1C surgery. RSNA and ARNA were recorded from the right or clipped kidney. C, Mean±SEM and individual data points of mean ABP, renal SNA, rectified/integrated ARNA, and ARNA discharge. Summary values were derived from 15-min averages for each variable. Summary data for female rats is illustrated in Figure S3. *P<0.05 sham vs 2K1C wild-type rats, #P<0.05 wild-type vs Trpv1−/− rats with 2K1C
Figure 6.
Figure 6.. Glomerular Filtration Rate (GFR) of Male Wild-Type and Transient Receptor Potential Vanilloid 1 Knockout (Trpv1−/−) Rats
Total GFR, total GFR normalized to 100 g body weight, left and right kidney GFR, and left and right kidney mass of male wild-type and Trpv1−/− rats with sham or 2-kidney-1-clip (2K1C) surgery. *P<0.05 sham vs 2K1C; #P<0.05 wild-type vs Trpv1−/−
See this image and copyright information in PMC

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