Activation of TRPV1-Expressing Renal Sensory Nerves of Rats with N-Oleoyldopamine Attenuates High-Fat-Diet-Induced Impairment of Renal Function.

Enhanced renal sympathetic nerve activity (RSNA) contributes to obesity-induced renal disease, while the role of afferent renal nerve activity (ARNA) is not fully understood. The present study tested the hypothesis that activating the transient receptor potential vanilloid 1 (TRPV1) channel in afferent renal nerves suppresses RSNA and prevents renal dysfunction and hypertension in obese rats. N-oleoyldopamine (OLDA, 1 ng/kg, daily) was administrated intrathecally (T8-L3) via an indwelled catheter to chronically activate, TRPV1-positive afferent renal nerves in rats fed a chow diet or high-fat diet (HFD) for 8 weeks. HFD intake significantly increased the body weight, impaired glucose and insulin tolerance, decreased creatinine clearance, and elevated systolic blood pressure in rats compared with the levels of the chow-fed rats (all p < 0.05). An intrathecal OLDA treatment for 8 weeks did not affect the fasting glucose level, glucose tolerance, and insulin tolerance in rats fed either chow or HFD. As expected, the chronic OLDA treatment significantly increased the levels of plasma calcitonin gene-related peptide and substance P and ARNA in the HFD-fed rats (all p < 0.05). Interestingly, the OLDA treatment decreased the urinary norepinephrine level and RSNA in rats fed HFD (both p < 0.05). Importantly, the OLDA treatment attenuated HFD-induced decreases in creatinine clearance and urinary Na+ excretion and increases in the plasma urea level, urinary albumin level, and systolic blood pressure at the end of an 8-week treatment (all p < 0.05). Taken together, the intrathecal administration of OLDA ameliorates the enhancement of RSNA, renal dysfunction, and hypertension in obese rats. These findings shed light on the roles of TRPV1-positive renal afferent nerves in obesity-related renal dysfunction and hypertension.

Knockout of Trpa1 accelerates age-related cardiac fibrosis and dysfunction.

Age-related cardiac fibrosis contributes to the development of heart failure with preserved ejection fraction which lacks ideal treatment. Transient receptor potential ankyrin 1 (TRPA1) is an oxidative stress sensor and could attenuate age-related pathologies in invertebrates. The present study aimed to test whether TRPA1 plays a role in age-related cardiac remodeling and dysfunction. The cardiac function and pathology of 12-week-old (young) and 52-week-old (older) Trpa1-/- mice and wild-type (WT) littermates were evaluated by echocardiography and histologic analyses. The expression levels of 84 fibrosis-related genes in the heart were measured by quantitative polymerase chain reaction array. Young Trpa1-/- and WT mice had similar left ventricular wall thickness, volume, and systolic and diastolic function. Older Trpa1-/- mice had significantly increased left ventricular internal diameter and volume and impaired systolic (lower left ventricular ejection fraction) and diastolic (higher E/A ratio and isovolumetric relaxation time) functions compared with older WT mice (P<0.05 or P<0.01). Importantly, older Trpa1-/- mice had enhanced cardiac fibrosis than older WT mice (P<0.05) while the two strains had similar degree of cardiac hypertrophy. Among the 84 fibrosis-related genes, Acta2, Inhbe, Ifng, and Ccl11 were significantly upregulated, while Timp3, Stat6, and Ilk were significantly downregulated in the heart of older Trpa1-/- mice compared with older WT mice. Taken together, we found that knocking out Trpa1 accelerated age-related myocardial fibrosis, ventricular dilation, and cardiac dysfunction. These findings suggest that TRPA1 may become a therapeutic target for preventing and/or treating cardiac fibrosis and heart failure with preserved ejection fraction in the elderly.

Activation of TRPV1 improves natriuresis and salt sensitivity in high-fat diet fed mice.

Western diet (WD) intake increases morbidity of obesity and salt-sensitive hypertension albeit mechanisms are largely unknown. We investigated the role of transient receptor potential vanilloid 1 (TRPV1) in WD intake-induced hypertension. TRPV1-/- and wild-type (WT) mice were fed a normal (CON) or Western diet (WD) for 16-18 weeks. Mean arterial pressure (MAP) after normal sodium glucose (NSG) loading with or without L-NAME (a NO synthase inhibitor) or N-oleoyldopamine (OLDA, a TRPV1agonist) was not different between the two strains on CON.WT or TRPV1-/- mice fed WD had increased MAP after NSG, with a greater magnitude in TRPV1-/- mice. OLDA decreased while L-NAME increased MAP in WT-WD but not in TRPV1-/--WD mice. The urinary nitrates plus nitrites excretion (UNOx), an indicator of renal NO production, was increased in both strains on CON after NSG. TRPV1 ablation with WD intake abolished NSG-induced increment in UNOx. OLDA further increased while L-NAME prevented NSG-induced increment in UNOx in WT-WD mice. Urinary sodium excretion was increased in both strains on CON and in WT-WD mice but not in TRPV1-/--WD mice after NSG. OLDA further increased while L-NAME prevented NSG-induced increases in sodium excretion in WT-WD but not in TRPV1-/--WD mice. Thus, TRPV1 ablation increases salt sensitivity during WD intake possibly via impaired renal NO production and sodium excretion. Activation of TRPV1 enhances renal NO production and sodium excretion, resulting in prevention of increased salt sensitivity during WD intake.

Ablation of TRPV1 Abolishes Salicylate-Induced Sympathetic Activity Suppression and Exacerbates Salicylate-Induced Renal Dysfunction in Diet-Induced Obesity.

Sodium salicylate (SA), a cyclooxygenase inhibitor, has been shown to increase insulin sensitivity and to suppress inflammation in obese patients and animal models. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel expressed in afferent nerve fibers. Cyclooxygenase-derived prostaglandins are involved in the activation and sensitization of TRPV1. This study tested whether the metabolic and renal effects of SA were mediated by the TRPV1 channel. Wild-type (WT) and TRPV1-/- mice were fed a Western diet (WD) for 4 months and received SA infusion (120mg/kg/day) or vehicle for the last 4 weeks of WD feeding. SA treatment significantly increased blood pressure in WD-fed TRPV1-/- mice (p < 0.05) but not in WD-fed WT mice. Similarly, SA impaired renal blood flow in TRPV1-/- mice (p < 0.05) but not in WT mice. SA improved insulin and glucose tolerance in both WT and TRPV1-/- mice on WD (all p < 0.05). In addition, SA reduced renal p65 and urinary prostaglandin E2, prostaglandin F1α, and interleukin-6 in both WT and TRPV1-/- mice (all p < 0.05). SA decreased urine noradrenaline levels, increased afferent renal nerve activity, and improved baroreflex sensitivity in WT mice (all p < 0.05) but not in TRPV1-/- mice. Importantly, SA increased serum creatinine and urine kidney injury molecule-1 levels and decreased the glomerular filtration rate in obese WT mice (all p < 0.05), and these detrimental effects were significantly exacerbated in obese TRPV1-/- mice (all p < 0.05). Lastly, SA treatment increased urine albumin levels in TRPV1-/- mice (p < 0.05) but not in WT mice. Taken together, SA-elicited metabolic benefits and anti-inflammatory effects are independent of TRPV1, while SA-induced sympathetic suppression is dependent on TRPV1 channels. SA-induced renal dysfunction is dependent on intact TRPV1 channels. These findings suggest that SA needs to be cautiously used in patients with obesity or diabetes, as SA-induced renal dysfunction may be exacerbated due to impaired TRPV1 in obese and diabetic patients.

Ablation of TRPV1-positive nerves exacerbates salt-induced hypertension and tissue injury in rats after renal ischemia-reperfusion via infiltration of macrophages.

Background: High-salt intake after renal ischemia/reperfusion (I/R) injury leads to hypertension and further renal injury, but the mechanisms are largely unknown. This study tested the hypothesis that degeneration of transient receptor potential vanilloid 1 (TRPV1)-positive nerves exacerbates salt-induced hypertension and renal injury after I/R via enhancing renal macrophage infiltration.Methods: Large dose of capsaicin (CAP, 100 mg/kg, subcutaneously) was used to degenerate rat TRPV1-positive nerves. Then, rats were subjected to renal I/R injury and fed with a low-salt (0.4% NaCl) diet for 5 weeks after I/R, followed by a high-salt (4% NaCl) diet for 4 weeks during which macrophages were depleted using liposome-encapsulated clodronate (LC, 1.3 ml/kg/week, intravenously).Results: The protein level of TRPV1 in the kidney was downregulated by renal I/R injury and was further decreased by CAP treatment. LC treatment did not affect the protein levels of renal TRPV1. After renal I/R injury, high-salt diet significantly increased renal macrophage infiltration, inflammatory cytokines (tumor necrosis factor-alpha and interleukin 1 beta), systolic blood pressure, the urine/water intake ratio, plasma creatine and urea levels, urinary 8-isoprostane, and renal collagen deposition. Interestingly, CAP treatment further increased these parameters. These increases were abolished by depleting macrophages with LC treatment.Conclusions: These data suggest that degenerating TRPV1-positive nerves exacerbates salt-induced hypertension and tissue injury in rats after renal I/R injury via macrophages-mediated renal inflammation.

Knockout of Trpa1 Exacerbates Renal Ischemia-Reperfusion Injury With Classical Activation of Macrophages.

BACKGROUND: Classically activated macrophages contribute to the development of renal ischemia-reperfusion injury (IRI). This study aimed to investigate the role of transient receptor potential ankyrin 1 (Trpa1), a regulator of macrophage activation, in IRI-induced acute kidney injury (AKI) by using the Trpa1 gene knockout (Trpa1-/-) mouse model. METHODS: Male 8-week-old Trpa1-/- mice and wild-type (WT) littermates were subjected to renal ischemia for 35 minutes by clamping bilateral renal pedicles under isoflurane anesthesia, and blood and tissue samples were collected 24 hours after reperfusion and analyzed with histological and molecular measurements. RESULTS: Following IRI, Trpa1-/- mice developed more deteriorated biochemical and morphological signs of AKI when comparing with WT mice. More classically activated M1 macrophages were found in the kidneys of Trpa1-/- mice comparing with WT mice after IRI, while the counts of alternatively activated M2 macrophages in the kidney were similar between the 2 strains after IRI. Furthermore, significantly higher expression levels of proinflammatory markers including interleukin-1 beta and tumor necrosis factor alpha were detected in the kidney of Trpa1-/- mice compared with WT mice after IRI. The levels of TRPA1 protein in the kidney of WT mice were also decreased after IRI. CONCLUSIONS: Our results show that ablation of Trpa1 exacerbates infiltration of classically activated macrophages, renal inflammation, and renal injury in mice after IRI. These findings suggest that activation of TRPA1 may protect against IRI-induced AKI via regulation of macrophage-mediated inflammatory pathway.

Relationship between blood pressure and kidney diseases in large randomized controlled trials: secondary analyses using SPRINT and ACCORD-BP trials.

Hypertension is a risk factor for acute kidney injury. In this study, we aimed to identify the optimal blood pressure (BP) targets for CKD and non-CKD patients. We analyzed the data of the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial (ACCORD BP) to determine the nonlinear relationship between BP and renal disease development using the Generalized Additive Model (GAM). Optimal systolic BP/diastolic BP (SBP/DBP) with lowest renal risk were estimated using GAM. Logistic regression was employed to find odds ratios (ORs) of adverse renal outcomes by three BP groups (high/medium/low). Both study trials have demonstrated a "U"-shaped relationship between BP and renal outcomes. For non-CKD patients in SPRINT trial, risk of 30% reduction in eGFR among intensive group patients with DBP ≤ 70 mmHg was significantly higher than the group with DBP between 71 and 85 mmHg (OR = 2.31, 95% CI = 1.51-3.53). For non-CKD patients in ACCORD trial, risk of doubling of serum creatinine (SCr) or >20 mL/min decrease in eGFR among intensive group patients with DBP ≤ 70 mmHg was significantly higher than the group with DBP between 71 and 85 mmHg (OR = 1.49, 95% CI = 1.12-1.99). For CKD patients in SPRINT trial, there are no significant differences in renal outcomes by different SBP/DBP levels. Our analysis of both SPRINT and ACCORD datasets demonstrated that lower-than-optimal DBP may lead to poor renal outcomes in non-CKD patients. Healthcare providers should be cautious of too low DBP level in intensive BP management due to poor renal outcomes for non-CKD patients.

Knockout of TRPV1 Exacerbates Ischemia-reperfusion-induced Renal Inflammation and Injury in Obese Mice.

BACKGROUND/AIM: Transient receptor potential vanilloid type 1 (TRPV1) has anti-inflammatory properties. The present study aimed to investigate the role of TRPV1 in renal inflammatory responses and tissue injury following renal ischemia-reperfusion (I/R) in diet-induced obese mice. MATERIALS AND METHODS: TRPV1 knockout and wild type mice were fed a normal or western diet (WD) for 23 weeks and were then subjected to renal I/R injury. RESULTS: TRPV1 knockout mice showed enhanced WD-induced renal macrophage infiltration and collagen deposition. Knocking out TRPV1 exacerbated renal I/R-induced increase of malondialdehyde, interleukin-6, monocyte chemoattractant protein-1, and NF-ĸB in obese mice. Similar results were observed in the expression of phosphorylated Smad1 and Smad2/3. Blockade of calcitonin gene-related peptide (CGRP) receptors with CGRP8-37 worsened the I/R-induced renal inflammation and injury. CONCLUSION: Our data indicate that preserving TRPV1 expression and function may prevent renal I/R injury in obesity likely through alleviating inflammatory responses.

TRPV1 Activation Prevents Renal Ischemia-Reperfusion Injury-Induced Increase in Salt Sensitivity by Suppressing Renal Sympathetic Nerve Activity.

BACKGROUND: Salt sensitivity is increased following renal Ischemia-Reperfusion (I/R) injury. We tested the hypothesis that high salt intake induced increase in Renal Sympathetic Nerve Activity (RSNA) after renal I/R can be prevented by activation of Transient Receptor Potential Vanilloid 1 (TRPV1). METHODS: Rats were fed a 0.4% NaCl diet for 5 weeks after renal I/R, followed by a 4% NaCl diet for 4 more weeks in four groups: sham, I/R, I/R +High Dose Capsaicin (HDC), and I/R+Low Dose Capsaicin (LDC). The low (1mg/kg) or high (100mg/kg) dose of capsaicin was injected subcutaneously before I/R to activate or desensitize TRPV1, respectively. RESULTS: Systolic blood pressure was gradually elevated after fed on a high-salt diet in the I/R and I/R+HDC groups but not in the I/R+LDC group, with a greater increase in the I/R+HDC group. Renal function was impaired in the I/R group and was further deteriorated in the I/R+HDC group but was unchanged in the I/R+LDC group. At the end of high salt treatment, afferent renal nerve activity in response to unilateral intra-pelvic administration of capsaicin was decreased in the I/R group and was further suppressed in the I/R+HDC group but was unchanged in the I/R+LDC group. RSNA in response to intrathecal administration of muscimol, a selective agonist of GABA-A receptors, was augmented in the I/R group and further intensified in the I/R+HDC group but was unchanged in the I/R+LDC group. Similarly, urinary norepinephrine levels were increased in the I/R group and were further elevated in the I/R+HDC group but unchanged in the I/R+LDC group. CONCLUSION: These data suggest that TRPV1 activation prevents renal I/R injury-induced increase in salt sensitivity by suppressing RSNA.

Protective Effects of TRPV1 Activation Against Cardiac Ischemia/ Reperfusion Injury is Blunted by Diet-Induced Obesity.

BACKGROUND: Activation of Transient Receptor Potential Vanilloid Subtype 1 (TRPV1) channels protects the heart from Ischemia/Reperfusion (I/R) injury through releasing Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP). The current study aimed to study the cardioprotective effects of TRPV1 in obesity. METHODS: TRPV1 gene knockout (TRPV1-/-) and Wild-Type (WT) mice were Fed a High-Fat Diet (HFD) or a control diet or for 20 weeks, and then the hearts were collected for I/R injury ex vivo. The hearts were mounted on a Langendorff apparatus and subjected to ischemia (30 min) and reperfusion (40 min) after incubated with capsaicin (10 nmol/L), CGRP (0.1 µmol/L) and SP (0.1 µmol/L). Then, Coronary Flow (CF), left ventricular peak positive dP/dt (+dP/dt), Left Ventricular Developed Pressure (LVDP) and Left Ventricular End-Diastolic Pressure (LVEDP) were measured. RESULTS: HFD intake remarkably reduced CF, +dP/dt and LVDP and elevated LVEDP in both strains (P<0.05). Treatment with capsaicin decreased infarct size, increased CF, +dP/dt and LVDP, and decreased LVEDP in WT mice on control diet (P<0.05), but did not do so in other three groups. Treatment with CGRP and SP decreased infarct size in both strains fed with control diet (P<0.05). In contrast, not all the parameters of cardiac postischemic recovery in HFD-fed WT and TRPV1-/- mice were improved by CGRP and SP. CONCLUSION: These results suggest that HFD intake impairs cardiac postischemic recovery. HFDinduced impairment of recovery is alleviated by CGRP in both strains and by SP only in TRPV1-/- mice, indicating that the effects of CGRP and SP are differentially regulated during HFD intake.

Protease-activated receptor 2 protects against myocardial ischemia-reperfusion injury through the lipoxygenase pathway and TRPV1 channels.

This study tests the hypothesis that the lipoxygenase (LOX) pathway mediates protease-activated receptor (PAR) 2-induced activation of the transient receptor potential vanilloid receptor 1 (TRPV1) to protect the heart from ischemia/reperfusion (I/R) injury. SLIGRL, a PAR2 activating peptide, was administered prior to reperfusion following left anterior descending coronary artery ligation in wild type (WT) and TRPV1 knockout (TRPV1-/-) mice. In a Langendorffly perfused heart I/R model, hemodynamic parameters, including left ventricular end-diastolic pressure, left ventricular developed pressure, coronary blood flow and left ventricular peak +dP/dt were evaluated after I/R. SLIGRL reduced the cardiac infarct size in WT and TRPV1-/- mice with a greater effect in the former strain (P<0.05). SLIGRL increased plasma levels of calcitonin gene-related peptide (CGRP) and substance P in WT (both P<0.05) but not in TRPV1-/- mice. Pretreatment with CGRP8-37 (a CGRP receptor antagonist) or RP67580 (a neurokinin-1 receptor antagonist) alone had no effect on SLIGRL-induced cardiac protection in either strain. However, combined administration of CGRP8-37 and RP67580 abolished SLIGRL-induced cardiac protection in WT but not in TRPV1-/- mice. Nordihydroguaiaretic acid (a general LOX inhibitor) and baicalein (a 12-LOX inhibitor), but not indomethacin (a cyclooxygenase inhibitor) and hexanamide (a selective cytochrome P450 epoxygenase inhibitor), abolished the protective effects of SLIGRL in WT (all P<0.05) but not in TRPV1-/- hearts. These data suggested that PAR2, possibly via 12-LOX, activates TRPV1 and leads to CGRP and substance P release to prevent I/R injury in the heart, indicating that the 12-LOX-TRPV1 pathway conveys cardiac protection to alleviate myocardial infarction.

TRPV1 Mediates Glucose-induced Insulin Secretion Through Releasing Neuropeptides.

BACKGROUND/AIM: Transient receptor potential vanilloid 1 (TRPV1)-expressing sensory nerves innervate the pancreatic islets. Sensory neuropeptides, including calcitonin gene-related peptide (CGRP) and substance P (SP), participate in insulin secretion. This study aimed to investigate the role of TRPV1 in glucose-induced insulin secretion. MATERIALS AND METHODS: TRPV1-/- and wild-type (WT) mice were fed a normal diet for 24 weeks. Glucose tolerance and insulin secretion were measured at the end of the experiments. RESULTS: TRPV1-/- mice had greater impairments in glucose tolerance and higher decrease in glucose-induced insulin secretion than WT mice. Capsaicin (a TRPV1 agonist) increased insulin secretion in WT, but not in TRPV1-/- mice. Glucose-induced insulin secretion was blunted in TRPV1-/- mice, and was attenuated by AMG9810 (a TRPV1 inhibitor), CGRP8-37 (a CGRP receptor antagonist), or RP67580 (a NK-1 receptor antagonist) in WT mice. Glucose-induced SP and CGRP release from WT pancreas was higher than that from TRPV1-/- pancreas. CONCLUSION: TRPV1 mediates glucose-induced insulin secretion likely through CGRP and SP release.

Knockout of TRPA1 exacerbates angiotensin II-induced kidney injury.

Macrophage-mediated inflammation plays a critical role in hypertensive kidney disease. Here, we investigated the role of transient receptor potential ankyrin 1 (TRPA1), a sensor of inflammation, in angiotensin II (ANG II)-induced renal injury. Subcutaneous infusion of ANG II (600 ng·min-1·kg-1) for 28 days was used to induce hypertension and renal injury in mice. The results showed that ANG II-induced hypertensive mice have decreased renal Trpa1 expression (P < 0.01), whereas ANG II receptor type 1a-deficient hypotensive mice have increased renal Trpa1 expression (P < 0.05) compared with their normotensive counterparts. ANG II induced similar elevations of systolic blood pressure in Trpa1-/- and wild-type (WT) mice but led to higher levels of blood urea nitrogen (P < 0.05), serum creatinine (P < 0.05), and renal fibrosis (P < 0.01) in Trpa1-/- mice than WT mice. Similarly, ANG II increased both CD68+/inducible nitric oxide synthase+ M1 and CD68+/arginase 1+ M2 macrophages in the kidneys of both Trpa1-/- and WT mice (all P < 0.01), with higher extents in Trpa1-/- mice (both P < 0.01). Compared with WT mice, Trpa1-/- mice had significantly increased expression levels of inflammatory cytokines and their receptors in the kidney. Cultured murine macrophages were stimulated with phorbol 12-myristate 13-acetate, which downregulated gene expression of TRPA1 (P < 0.01). A TRPA1 agonist, cinnamaldehyde, significantly inhibited phorbol 12-myristate 13-acetate-stimulated expression of IL-1ß and chemokine (C-C motif) ligand 2 in macrophages, which were attenuated by pretreatment with a TRPA1 antagonist, HC030031. Furthermore, activation of TRPA1 with cinnamaldehyde induced apoptosis of macrophages. These findings suggest that TRPA1 may play a protective role in ANG II-induced renal injury, likely through inhibiting macrophage-mediated inflammation.

TRPV1 protects renal ischemia-reperfusion injury in diet-induced obese mice by enhancing CGRP release and increasing renal blood flow.

BACKGROUND: Obesity is a major risk factor for end-stage renal disease. Using transient receptor potential vanilloid 1 knockout (TRPV1-/-) mice, we tested the hypothesis that TRPV1 protects against obesity-induced exacerbation of renal ischemia-reperfusion (I/R) injury. METHODS: TRPV1-/- and wild-type (WT) mice were fed a chow or Western diet (WD) for 22-23 weeks. After that, mice were subjected to renal I/R injury, and renal cortical blood flow (CBF) and medullary blood flow (MBF) were measured. RESULTS: The Western diet significantly increased body weight and fasting blood glucose levels in both TRPV1-/- and WT mice. WD-induced impairment of glucose tolerance was worsened in TRPV1-/- mice compared with WT mice. WD intake prolonged the time required to reach peak reperfusion in the cortex and medulla (both P < 0.05), decreased the recovery rate of CBF (P < 0.05) and MBF (P < 0.05), and increased blood urea nitrogen, plasma creatinine, and urinary 8-isoprostane levels after I/R in both mouse strains, with greater effects in TRPV1-/- mice (all P < 0.05). Renal I/R increased calcitonin gene-related peptide (CGRP) release in WT but not in TRPV1-/- mice, and WD attenuated CGRP release in WT mice. Moreover, blockade of CGRP receptors impaired renal regional blood flow and renal function in renal I/R injured WT mice. CONCLUSION: These results indicate that TRPV1 plays a protective role in WD-induced exacerbation of renal I/R injury probably through enhancing CGRP release and increasing renal blood flow.

Ablation of TRPV1 Elevates Nocturnal Blood Pressure in Western Diet-fed Mice.

BACKGROUND: This study tested the hypothesis that genetically ablation of transient receptor potential vanilloid type 1 (TRPV1) exacerbates impairment of baroreflex in mice fed a western diet (WD) and leads to distinct diurnal and nocturnal blood pressure patterns. METHODS: TRPV1 gene knockout (TRPV1-/-) and wild-type (WT) mice were given a WD or normal diet (CON) for 4 months. RESULTS: Capsaicin, a selective TRPV1 agonist, increased ipsilateral afferent renal nerve activity in WT but not TRPV1-/- mice. The sensitivity of renal sympathetic nerve activity and heart rate responses to baroreflex were reduced in TRPV1-/--CON and WT-WD and further decreased in TRPV1-/--WD compared to the WT-CON group. Urinary norepinephrine and serum insulin and leptin at day and night were increased in WT-WD and TRPV1-/--WD, with further elevation at night in TRPV1-/--WD. WD intake increased leptin, IL-6, and TNF-α in adipose tissue, and TNF-α antagonist III, R-7050, decreased leptin in TRPV1-/--WD. The urinary albumin level was higher in TRPV1-/--WD than WT-WD. Blood pressure was not different during daytime among all groups, but increased at night in the TRPV1-/--WD group compared with other groups. CONCLUSIONS: TRPV1 ablation leads to elevated nocturnal but not diurnal blood pressure, which is probably attributed to further enhancement of sympathetic drives at night.

Activation of TRPV1 Prevents Salt-Induced Kidney Damage and Hypertension After Renal Ischemia-Reperfusion Injury in Rats.

BACKGROUND/AIMS: High-salt intake after recovery from renal ischemia-reperfusion (I/R) injury leads to hypertension with severe renal damage. Transient receptor potential vanilloid type 1 (TRPV1) channels have been involved in the regulation of inflammation and oxidative stress following ischemic organ injury. We tested the hypothesis that activation of TRPV1 conveys preconditioning protection to the kidney subjected to I/R. METHODS: TRPV1 was activated or down-regulated by subcutaneous injection of a low (1mg/kg) or high (100mg/kg) dose of capsaicin, respectively, 3 hours before ischemia. Rats were fed a 0.4% NaCl diet for 5 weeks after I/R followed by a 4% NaCl diet for 4 more weeks in 4 groups: sham, I/R, I/R+high-dose capsaicin (HCap), and I/R+low-dose capsaicin (LCap). RESULTS: Renal TRPV1 expression was decreased in I/R rats (P< 0.05) and further reduced in I/R+HCap group (P< 0.05) but unchanged in I/R+LCap rats compared with the sham group. Blood pressure were elevated in I/R rats (P< 0.05) and further increased in I/R+HCap group (P< 0.05) but unchanged in I/R+LCap rats compared with sham. Renal function was impaired in I/R rats (P< 0.05) and further deteriorated in I/R+HCap group (P< 0.05) but unchanged in I/R+LCap group. Renal inflammatory responses, oxidative stress, and renal collagen deposition were augmented in I/R rats (all P< 0.05) and further intensified in I/R+HCap group (all P< 0.05) but unchanged in I/R+LCap group. CONCLUSION: Activation of TRPV1 plays an anti-inflammatory and anti-oxidative stress role in preventing renal tissue damage and salt-induced hypertension after I/R injury, indicating that TRPV1 conveys preconditioning protection that may have therapeutic implication.

Selective ablation of TRPV1 by intrathecal injection of resiniferatoxin in rats increases renal sympathoexcitatory responses and salt sensitivity.

This study tested the hypothesis that selective ablation of transient receptor potential vanilloid type 1 (TRPV1)-positive nerve fibers by intrathecal injection of resiniferatoxin (RTX) enhances renal sympathoexcitatory responses and salt sensitivity. Intrathecal injection of RTX (1.8 µg/kg) to the levels of lower thoracic and upper lumbar spinal cord (T8-L3) increased mean arterial pressure (MAP) in rats fed a normal (NS, 1% NaCl) or high-sodium (HS, 8% NaCl) diet for 4 weeks compared to vehicle-treated rats (NS: 121 ± 2 vs. 111 ± 2; HS: 154 ± 2 vs. 134 ± 2 mm Hg, both P < 0.05), with a greater increase in HS compared to NS rats (9 ± 1% vs. 15 ± 1%, P < 0.05). TRPV1 contents were decreased in T8-L3 segments of spinal dorsal horn but not in corresponding dorsal root ganglia and the kidney following RTX treatment (P < 0.05). Selective activation of GABA-A receptors with intrathecal T8-L3 segment-injection of muscimol (3 nmol/kg) decreased renal sympathetic nerve activity and increased urinary excretion in both NS and HS rats, with a greater effect in RTX-treated compared to vehicle-treated rats (P < 0.05). Chronic activation of GABA-A receptors with muscimol (50 mg/kg/day × 2, p.o.) abolished RTX treatment-induced pressor effects in NS and HS rats. GAD65/67, a GABA synthetase, in the spinal cord was downregulated and tyrosine hydroxylase in the kidney upregulated in NS or HS rats treated with RTX (P < 0.05). Thus, selective ablation of TRPV1-positive central terminals of sensory neurons plays a prohypertensive role possibly via inhibition of spinal GABA system especially with HS intake, suggesting that activation of TRPV1 in central terminals of sensory neurons may convey an antihypertensive effect.

Knockout of TRPV1 Exacerbates Left Ventricular Diastolic Dysfunction Induced by A High-fat Diet in Mice.

BACKGROUND: Transient Receptor Potential Vanilloid 1 (TRPV1) channels in sensory nerves have anti-oxidative properties and counteract obesity and diabetes that are associated with diastolic dysfunction with preserved ejection fraction. We tested the hypothesis that TRPV1 knockout exacerbates high-fat diet (HFD)-induced glucose intolerance and diastolic dysfunction. METHOD: Trpv1-/- and wild-type (WT) mice were fed chow diet or HFD for 20 weeks. Then, we performed the intraperitoneal glucose tolerance test, measured the heart function through transthoracic echocardiography and Langendorff heart perfusion system, analyzed cardiac histology, and measured the myocardial superoxide production and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. RESULTS: HFD increased body weight, heart weight, and levels of fasting glucose, insulin, and leptin in both strains, with no differences between two strains. HFD impaired glucose tolerance in both strains with a more profound effect on Trpv1-/- than WT mice. HFD increased left ventricular (LV) internal diameter in diastole in both strains, while increased LV posterior wall thickness in diastole in Trpv1-/- but not in WT mice. HFD increased LV end-diastolic pressure in both strains with a further increase in Trpv1-/- mice, while decreased -dP/dt in Trpv1-/- but not in WT mice. HFDinduced cardiac collagen deposition and superoxide production were enhanced in Trpv1-/- mice. HFD upregulated cardiac p22phox in both strains, while increased p47phox in Trpv1-/- but not in WT mice. CONCLUSION: In summary, TRPV1 knockout exacerbates HFD-induced glucose intolerance, cardiac oxidative stress and collagen deposition, leading to aggravated LV diastolic dysfunction.

Genetic ablation of TRPV1 exacerbates pressure overload-induced cardiac hypertrophy.

Transient receptor potential vanilloid 1 (TRPV1) channels expressed in sensory nerves may regulate vascular tone and cardiovascular function via their anti-inflammatory effects by releasing neuropeptide calcitonin gene-related peptide (CGRP). Inflammation plays a role in the progression of cardiac hypertrophy and TRPV1 activation may be key to cardiac inflammatory processes. The aim of this study was to test the hypothesis that TRPV1 modulates inflammatory processes to protect the heart from pressure overload-induced hypertrophy and inflammatory responses. Trpv1 knockout (Trpv1-/-) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) or sham operation. Four weeks after TAC, WT and Trpv1-/- mice had developed left ventricular (LV) hypertrophy with increased LV mass, fibrosis and infiltration of macrophages as well as increased secretion of tumor necrosis factor α, interleukin-6 from cardiac tissue (all P < 0.05), those were higher in Trpv1-/- than in WT mice with TAC (all P < 0.05). In addition, decreases of LV ejection fraction and fractional shortening were greater in Trpv1-/- than in WT mice (both P < 0.05). Moreover, atrial natriuretic peptide level was greater in Trpv1-/- than in WT mice with TAC (P < 0.05). Compared to sham control, TAC procedure significantly increased cardiac TRPV1 expression and CGRP release in WT mice (both P < 0.05), but not in Trpv1-/- mice. These results demonstrate that Trpv1 gene deletion results in excessive inflammation, exaggerates cardiac hypertrophy, and deteriorates cardiac function after TAC, which may be due to abnormal cardiac remodeling and decreased CGRP in the absence of TRPV1.