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Research Article
Originally Published 2 June 2014
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Transient Receptor Potential Vanilloid 1 Activation by Dietary Capsaicin Promotes Urinary Sodium Excretion by Inhibiting Epithelial Sodium Channel α Subunit–Mediated Sodium Reabsorption

Li Li, Fei Wang, Xing Wei, Yi Liang, Yuanting Cui, Feng Gao, Jian Zhong, … Show All … , Yunfei Pu, Yu Zhao, Zhencheng Yan, William J. Arendshorst, Bernd Nilius, Jing Chen, Daoyan Liu, and Zhiming ZhuAuthor Info & Affiliations
Hypertension
Volume 64, Number 2
https://doi.org/10.1161/HYPERTENSIONAHA.114.03105
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Abstract

High salt (HS) intake contributes to the development of hypertension. Epithelial sodium channels play crucial roles in regulating renal sodium reabsorption and blood pressure. The renal transient receptor potential vanilloid 1 (TRPV1) cation channel can be activated by its agonist capsaicin. However, it is unknown whether dietary factors can act on urinary sodium excretion and renal epithelial sodium channel (ENaC) function. Here, we report that TRPV1 activation by dietary capsaicin increased urinary sodium excretion through reducing sodium reabsorption in wild-type (WT) mice on a HS diet but not in TRPV1–/– mice. The effect of capsaicin on urinary sodium excretion was involved in inhibiting αENaC and its related with-no-lysine kinase 1/serum- and glucocorticoid-inducible protein kinase 1 pathway in renal cortical collecting ducts of WT mice. Dietary capsaicin further reduced the increased αENaC activity in WT mice attributed to the HS diet. In contrast, this capsaicin effect was absent in TRPV1–/– mice. Immunoprecipitation study indicated αENaC specifically coexpressed and functionally interact with TRPV1 in renal cortical collecting ducts of WT mice. Additionally, ENaC activity and expression were suppressed by capsaicin-mediated TRPV1 activation in cultured M1-cortical collecting duct cells. Long-term dietary capsaicin prevented the development of high blood pressure in WT mice on a HS diet. It concludes that TRPV1 activation in the cortical collecting ducts by capsaicin increases urinary sodium excretion and avoids HS diet–induced hypertension through antagonizing αENaC-mediated urinary sodium reabsorption. Dietary capsaicin may represent a promising lifestyle intervention in populations exposed to a high dietary salt intake.

Introduction

The pathogenesis of hypertension is caused by both genetic susceptibility and environmental risk factors.1 One of major environmental factors for hypertension is high-sodium or low-potassium dietary intake.2 Maintenance of a constant intravascular fluid volume and blood pressure depends on the kidneys’ ability to regulate the urinary sodium excretion (UNaV).3 Several renal sodium transporters, such as the thiazide-sensitive NaCl cotransporter (NCC) and the amiloride-sensitive epithelial sodium channel (ENaC), play crucial roles in regulating renal sodium reabsorption and blood pressure.4 Multigene kinases, including Ste20-related proline–alanine–rich kinase (SPAK), with-no-lysine kinase (WNK) 4 and 1, oxidative stress response kinase 1 (OSR1), and serum- and glucocorticoid-inducible protein kinase 1 (SGK1), regulate renal electrolyte transport. Abnormal signaling pathways attributable to aberrations of these kinases can result in renal sodium retention and hypertension.5 Currently, strategies to prevent the development of hypertension include avoidance of a high-salt (HS) diet and increased vegetables intake in general population. In addition, thiazide diuretics are commonly used to treat patients with hypertension through inhibiting renal sodium reabsorption in the distal convoluted tubule, thereby increasing the UNaV and reducing extracellular fluid volume.6 However, nondrug intervention–mediated UNaV is scarcely studied.
The transient receptor potential vanilloid 1 (TRPV1) cation channel is a polymodal nonselective cation channel that can be specifically activated by heat or capsaicin, a major pungent ingredient in hot peppers.7 We recently reported that TRPV1 activation by chronic dietary capsaicin improves endothelial function and lowers blood pressure in genetically hypertensive rats.8 Several studies showed that TRPV1 is expressed in the kidneys and is involved in renal sodium handling.9 Li and Wang9 showed that NCC but not ENaC was functionally upregulated in the kidneys of Wistar rats subjected to acute capsaicin-sensitive sensory nerve degeneration plus HS intake. It is unknown how chronic dietary capsaicin affects renal sodium excretion and blood pressure during long-term HS diet. In this study, we hypothesized that TRPV1 activation by dietary capsaicin contributes to renal benefits through inhibiting sodium transport. Thus, we examined this hypothesis in vitro and in vivo.

Materials and Methods

Detailed methods and reagents used can be found in the online-only Data Supplement.
Culture of the M1 cortical collecting duct (CCD) cell line, intracellular free calcium and sodium measurement, immunoprecipitation, immunoblotting analysis, blood pressure and urinay sodium excretion measurement, and standardized techniques were performed as described previously.
All mice (C57BL/6 wild-type [WT] mice and TRPV1–/– mice) were purchased from the Jackson Laboratory (Bar Harbor, Maine). Procedures were performed in accordance with protocols approved by the Institutional Animal Care and Research Advisory Committee.
The data are expressed as the mean±SEM from 5 to 8 independent experiments or mice. Comparisons between groups were analyzed using Kruskal–Wallis tests followed by the Mann–Whitney U test for multiple comparisons as appropriate with the Bonferroni correction (SPSS15.0 software; SPSS Inc, Chicago, IL). For all analyses, 2-sided P values <0.05 were considered to indicate statistical significance.

Results

Functional TRPV1 Is Expressed in the Mouse CCD and Promotes the UNaV by Dietary Capsaicin

To validate the presence of TRPV1 in the renal tubules and epithelial cells, mouse renal CCDs were isolated by microdissection. The expression of TRPV1 protein was detected by immunoblotting in freshly isolated CCD of WT mice and cultured M1-CCD cells; it was absent in CCD of TRPV1–/– mice (Figure S1A in the online-only Data Supplement). The colocalization of TRPV1 and αENaC in the M1-CCD cells and mice CCDs were demonstrated by immunofluorescence staining (Figure 1A and 1B). TRPV1 belongs to a family of nonselective cation channels, displaying high Ca2+ permeability. Administration of capsaicin, a TRPV1-specific agonist, caused a dose-dependent increase in the cytosolic free calcium concentration ([Ca]2+i) in M1-CCD cells. Specific blockade of TRPV1 by 5′-iodoresiniferatoxin inhibited the capsaicin-induced [Ca]2+i increase (Figure 1C). Thus, functional TRPV1 is localized to the mouse renal CCD. To examine whether chronic activation of TRPV1 would affect renal function, WT and TRPV1–/– mice were fed with a HS diet or a HS diet plus capsaicin (HSC) for 10 months. Capsaicin treatment significantly increased the UNaV of WT mice on a HS diet compared with the mice on a normal diet (ND) and the HS diet. However, capsaicin had no effects on UNaV in TRPV1–/– mice (Figure 1D). Dietary capsaicin had no effect on the urine volume in either group of mice consuming a HSC diet compared with the mice on a HS diet (Figure 1E). Hyperplasia of CCDs was observed in WT mice on HS diet but not on HSC diet. The capsaicin effect was absent in TRPV1–/– mice (Figure S1B). Thus, long-term dietary capsaicin caused an increase in UNaV that appeared to be mediated by TRPV1 activation.
Figure 1. Transient receptor potential vanilloid 1 (TRPV1) expression and effect of dietary capsaicin on urinary sodium excretion (UNaV). TRPV1 and α subunit of epithelial sodium channel (αENaC) colocalize in the (A) M1-cortical collecting duct (CCD) cells and (B) mice renal CCDs. 4’,6-diamidino-2-phenylindole (DAPI) indicates cell nucleus. Scale bar, 25 μm. Images are representative of 3 separate experiments. C, Representative curves (left) show [Ca]2+i changes induced by capsaicin with or without 5′-iodoresiniferatoxin (iRTX), the TRPV1 receptor antagonist, in the M1-CCD cells. The summary data (right) show the maximal stimulated changes of [Ca]2+i (25–125 seconds) from the baseline (0–25 seconds). The control group represents the M1-CCD cells without any stimulation. Summary data are presented as the mean±SEM for 5 independent experiments. *P<0.05 vs capsaicin 10 μmol/L; #P<0.05 vs capsaicin 1 μmol/L. UNaV (D) and 24-hour urine volume (E) of wild-type (WT) and TRPV1–/– mice fed on a normal diet (ND), high-salt (HS) diet, and HS diet plus capsaicin (HSC). Data are presented as the mean±SEM; n=6. **P<0.01 vs WT ND; #P<0.05 vs WT HS. Cap indicates capsaicin; and CON, control.

NCC and Its Regulating Pathways Are Not Involved in Dietary Capsaicin–Induced Sodium Excretion

Next, we examined which specific renal sodium transporter and regulatory pathway are involved in the action of capsaicin. OSR1 and SPAK activate NCC and WNK-OSR1/SPAK-NCC cooperates with aldosterone system, including the ENaC in regulating renal electrolyte transport and blood pressure. Our experiments showed that 24-hour UNaV was significantly increased after injection of the NCC inhibitor, hydrochlorothiazide, in HS diet and HSC diet compared with ND (Figure 2A). We observed that a HS diet significantly increased the expression of renal NCC and its regulatory kinases, WNK4, OSR1, and SPAK, changes which were not influenced by chronic dietary capsaicin in CCDs from WT mice (Figure 2B and 2C; Figure S2A and 2B). We further confirmed these results in vitro. It showed that high concentration of NaCl (10 mmol/L) upregulated NCC, WNK4, OSR1, and SPAK in cultured M1-CCD cells. Furthermore, capsaicin had no effects on those protein expressions (Figure S3A). Collectively, these results suggest that dietary capsaicin mediated the UNaV is not involved in the expressions of NCC and its regulatory kinases.
Figure 2. Lack of effect of dietary capsaicin on NaCl cotransporter (NCC)-mediated urinary sodium excretion (UNaV) and its related kinases A, Representative curves (left) show the individual 24-hour UNaV of wild-type (WT) mice fed on normal diet (ND), high-salt (HS) diet, and HS diet plus capsaicin (HSC) before and after hydrochlorothiazide (HCTZ) injection (12.5 mg/kg, intraperitoneal). The columns (right) show the changes in 24-hour UNaV before and after HCTZ injection. Immunoblots of (B) NCC and (C) with-no-lysine kinase (WNK) 4 in the renal cortical collecting ducts of WT mice. The values are presented as the mean±SEM for 6 mice. *P<0.05, **P<0.01 vs ND. The densitometric values of protein expressions are all normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

Dietary Capsaicin Reduces the Renal Sodium Reabsorption Through Inhibiting WNK1/SGK1/αENaC Pathway

We tested whether activation of TRPV1 affects ENaC function. The natriuretic effect of the ENaC blocker amiloride injection of WT mice on a HS diet was significantly greater than that of the mice fed a ND. Dietary capsaicin decreased the UNaV changes in WT mice but not TRPV1–/– mice on a HS diet (Figure 3A and 3B). The HS diet significantly increased the expressions of α and βENaC both in WT and TRPV1–/– mice CCDs (Figure 3C; Figure S2C). Dietary capsaicin reduced αENaC expression but no other isoforms of ENaCs in the CCDs of WT mice but not TRPV1–/– mice on a HS diet (Figure 3C; Figure S2C). The expressions of ENaC regulatory kinases, WNK1, and SGK1 in CCDs were upregulated in WT mice on a HS diet and inhibited by dietary capsaicin. However, these changes were not found in CCDs of TRPV1–/– mice on a HSC diet administration (Figure 3D). The present results indicate that activation of TRPV1 by dietary capsaicin antagonized renal sodium reabsorption through inhibition of αENaC and its related WNK1/SGK1 pathway.
Figure 3. Effect of dietary capsaicin on α subunit of epithelial sodium channel (αENaC) mediated the urinary sodium excretion (UNaV) through with-no-lysine kinase (WNK) 1/serum- and glucocorticoid-inducible protein kinase 1 (SGK1) pathway. Representative curves (left) show the individual 24-hour UNaV of (A) wild-type (WT) and (B) TRPV1–/– mice before and after amiloride injection (3 mg/kg, intraperitoneal). The columns (right) show the changes in 24-hour UNaV before and after amiloride injection. C, Immunoblots of αENaC (75 kDa) in the cortical collecting ducts (CCDs) of WT and TRPV1–/– mice fed on normal diet (ND), high-salt (HS) diet, and HS diet plus capsaicin (HSC). D, Immunoblots of WNK1 (250 kDa) and SGK1 (55 kDa) in CCDs from WT and TRPV1–/– mice. The values are presented as the mean±SEM for 6 to 8 mice. *P<0.05, **P<0.01 vs WT ND; #P<0.05, ##P<0.01 vs WT HS; ΔP<0.05, ΔΔP<0.01 vs TRPV1–/– ND. The densitometric values of protein expressions are all normalized to GAPDH. TRPV1 indicates transient receptor potential vanilloid 1.

TRPV1 Regulates αENaC Activity and Expression in CCD Cells

To determine whether the effects of the high salt and capsaicin on renal αENaC are involved in the action of TRPV1, cultured M1-CCD cells were incubated with additional 10 mmol/L NaCl (HS), 10 mmol/L NaCl plus 1 μmol/L capsaicin (HSC), and with or without 1 μmol/L 5′-iodoresiniferatoxin for 24 hours. It showed that high concentration of NaCl reduced TRPV1 but increased αENaC expressions in M1-CCD cells. However, capsaicin upregulated TRPV1 and reduced αENaC expressions in M1-CCD cells, which was inhibited by TRPV1-specific blockade, 5′-iodoresiniferatoxin (Figure 4A). Immunoprecipitation showed that αENaC interacted specifically with the immobilized TRPV1 in CCDs from WT mice fed with ND, HS, and HSC diet (Figure 4B). To further test whether TRPV1 activation by capsaicin suppressed αENaC activity, we performed the measurement of Na+ uptake in the cytosol of M1-CCD cells. On the acute addition of extracellular 100 mmol/L NaCl, the cytosolic fluorescence intensity ratio of M1-CCD cells treated with NaCl plus capsaicin (HSC) decreased compared with only NaCl (HS) treatment for 24 hours. The 5′-iodoresiniferatoxin increased Na+ uptake in the cytosol antagonizing capsaicin effect (Figure 4C). These data suggest that αENaC activity can be suppressed by capsaicin-mediated activation of TRPV1.
Figure 4. Interaction between transient receptor potential vanilloid 1 (TRPV1) and α subunit epithelial sodium channel (αENaC). A, Immunoblots of TRPV1 and αENaC in the M1-cortical collecting ducts (CCDs) cells treated with dimethyl sulfoxide (DMSO) (control), NaCl (HS, 10 mmol/L), NaCl plus capsaicin (HSC, capsaicin 1 μmol/L), or HSC plus 5′-iodoresiniferatoxin (iRTX) (HSC + iRTX, 1 μmol/L) for 24 hours. The values are presented as the mean±SEM for 5 independent experiments. *P<0.05 vs control; #P<0.05 vs HS; ΔP<0.05 vs HSC. The densitometric values of protein expression are all normalized to GAPDH. B, Immunoprecipitation (IP) with TRPV1 and αENaC antibodies on CCD isolated from wild-type (WT) mice. The immunoblot bands are representative of 6 separate experiments. C, Representative curves (left) show [Na+]i changes of the M1-CCD cells treated with DMSO (control), NaCl (HS, 10 mmol/L), NaCl plus capsaicin (HSC, capsaicin 1 μmol/L), or HSC plus iRTX (HSC + iRTX, 1 μmol/L) for 24 hours. The summary data (right) show the mean stimulated changes of [Na+]i by acute stimulation with 100 mmol/L NaCl (150–200 seconds) from the baseline (0–50 seconds). Summary data are presented as the mean±SEM for 5 independent experiments. *P<0.05 vs control, #P<0.05 vs HS, ΔP<0.05 vs HSC. CON indicates control; ND, normal diet; and SBP, systolic blood pressure.

TRPV1 Activation by Dietary Capsaicin Reduces HS Diet–Induced High Blood Pressure

Consistent with the previous studies, the systolic blood pressure was not different between the ND and HS diet groups in WT and TRPV1–/– mice until the sixth month.10 But the systolic blood pressure of WT and TRPV1–/– mice fed on a HS diet was significantly higher than that of the ND group after 8-month intervention. Because chronic activation of TRPV1 by dietary capsaicin inhibited sodium reabsorption, we asked whether TRPV1 activation by capsaicin reduced blood pressure. Capsaicin significantly lowered tail systolic blood pressure in WT mice on a HS diet after the eighth month (Figure 5A and 5B). Chronic dietary capsaicin also lowered 24-hour ambulatory arterial pressure in WT HS group mice after 10-month treatment (Figure 5C and 5D). Importantly, the hypotensive effect of capsaicin was absent in TRPV1–/– mice (Figure 5A–5D). Thus, long-term dietary capsaicin lowers the blood pressure of mice on a HS diet in a TRPV1-dependent manner.
Figure 5. Effect of dietary capsaicin on blood pressure and its related biochemaical parameters. A, The time courses show that the tail systolic blood pressures (SBP) of wild-type (WT) and TRPV1–/– mice are detected every 2 months during the 10 treating months with normal diet (ND), high-salt (HS) diet, and HS diet plus capsaicin (HSC). *P<0.05 vs ND; #P<0.05 vs HS. B, The tail SBPs of WT and TRPV1–/– mice are detected on the 10th treating month. *P<0.05 vs WT ND; #P<0.05 vs WT HS. SBP (C) and diastolic blood pressure (D) are determined for 24 hours using radiotelemetry in WT (left) and TRPV1–/– (right) mice on the 10th month. *P<0.05 vs ND; #P<0.05 vs HS. Plasma aldosterone (E) and urinary chloride excretion (F) of WT and TRPV1–/– mice. **P<0.01 vs WT ND; ΔΔP<0.01 vs TRPV1–/– ND. Data are presented as the mean±SEM; n=6 to 8. TRPV1 indicates transient receptor potential vanilloid 1.
Plasma aldosterones were lower in mice on a HS and HSC diet compared with mice on a ND diet in WT and TRPV1-/-mice (Figure 5E). The urinary chloride excretion and volume of water intake were higher in mice on a HS or HSC compared with mice on an ND in WT and TRPV1-/-mice (Figure 5F; Table S1). However, the plasma sodium, potassium and chloride, urinary potassium, and food intake were not different among each group of WT and TRPV1–/– mice (Table S1).

Discussion

Our study demonstrates that high-salt intake increased UNaV and blood pressure through upregulating the expressions of αENaC, WNK1, and SGK1 in mouse CCD in vivo. A major new finding was that activation of TRPV1 through chronic capsaicin treatment inhibited αENaC activity and reduced αENaC-mediated sodium reabsorption. Capsaicin activation of TRPV1 reduced αENaC expression both in vivo and in vitro as well as its regulatory kinases, WNK1 and SGK1, in renal CCDs of WT mice but not TRPV1–/– mice. Despite the low bioavailability of capsaicin, plasma concentration of capsaicin reached a peak of ≈10 ng/mL at the first hour,8 and chronic capsaicin treatment lowered blood pressure in WT mice on a HS diet in a TRPV1-dependent manner.
Renal sodium handling plays an important role in the maintenance of electrolyte excretion and body fluid volume and the regulation of blood pressure.11 Several apical sodium transporters are responsible for renal tubular reabsorption of sodium. Examples include type 3 Na/H exchanger in the proximal tubule, the thiazide-sensitive NCC in the distal convoluted tubule, and the amiloride-sensitive ENaC in the connecting tubule and collecting duct.12 Among transporters, ENaC plays an important role in long-term modulation of sodium balance and blood pressure.13 ENaC is a heteromeric channel composed of 3 similar but distinct subunits, α, β, and γ, with the α-subunit being critical to the formation of the ion permeating pore.14 Several studies have shown that HS diet increases ENaC activity in the kidney.15,16 However, αENaC level also reduces in mice fed on a HS diet.17 Sodium reabsorption elevation could be associated with the increase in distal nephron sodium in this status. Local angiotensin II might affect renal αENaC activity through normal paracrine and hormonal regulation of sodium reabsorption to high-salt intake.18 Our results showed that high-salt intake increased renal αENaC activity in the mouse CCD and the specific ENaC blocker amiloride magnified the increase in sodium excretion during HS diet. It is well known that mutations in ENaC can cause Liddle syndrome, a severe but rare form of heritable hypertension. High-salt intake affects renal ENaC activity, and the ENaC expression level may constitute the critical role of ENaC in salt-sensitive hypertension.19 However, how to restore ENaC dysfunction with high-salt intakes remains an obstacle. For patients with hypertension, thiazide and loop diuretics and amiloride are used to promote the UNaV by inhibiting sodium/chloride reabsorption, which involves in NCC, Na/K/2Cl cotransporter, and ENaC. For the general population, the Dietary Approaches to Stop Hypertension (DASH) trial convincingly revealed a dose-dependent decrease in blood pressure in response to reduced salt intake.2 Thus, it is interesting to explore whether dietary factors have a beneficial impact on renal sodium reabsorption in high-risk populations exposed to a high dietary salt intake.
Several studies have shown that capsaicin and its target, TRPV1, are implicated in hypertension.20 The renal sensory nerves that express TRPV1, and various neuropeptides, including potent vasodilators, are released on TRPV1 activation.21 Rats develop salt-sensitive hypertension after TRPV1 sensory degeneration by capsaicin treatment.22 Induction of hypertension by deoxycorticosterone acetate treatment in TRPV1–/– mice aggravated kidney damage.23 Mutants of TRPV1 not only detected NaCl in the presence of amiloride but also preferred NaCl over water at concentrations avoided by the WT mice.24 Long-term stimulation of TRPV1 by capsaicin can activate protein kinase A, which contributes to increased endothelial nitric oxide synthase phosphorylation, improves vasorelaxation, and lowers blood pressure in genetically hypertensive rats.8 Chronic administration of capsaicin reduced the HS diet–induced endothelial dysfunction and nocturnal hypertension in part by preventing the generation of superoxide anions and NO reduction in mesenteric arteries in WT mice.25 Several studies show the benefits of chili pepper in human. Long-term consumption of a diet high in chilies has been shown to improve arterial function in human.26 People who like spicy foods have lower blood pressure in a cross-sectional study.27 Consumption of spicy foods reportedly promotes negative energy balance, augments energy expenditure, enhances fat oxidation, and suppresses orexigenic sensations.28
The current results show that chronic capsaicin significantly increased UNaV and lowered blood pressure in mice. In contrast, these beneficial effects of capsaicin were absent in TRPV1–/– mice. Which mechanism is responsible for the TRPV1 effect? Our study showed that TRPV1 activation by capsaicin inhibited ENaC activity in the CCD tissue and cell. ENaC can be regulated by a variety of factors, including hormones and several kinases such as SGK1 and WNK1. Also, WNK1 can activate SGK1 to regulate ENaC.29 Activation of TRPV1 channel activates protein kinase C, phospholipase C, and calmodulin-dependent kinase 2, etc and, in turn, regulates TRPV1 activity through increasing the intracellular calcium level.30 Activation of phospholipase C/protein kinase C can inhibit ENaC activity in several cells.31 ENaC activity increases in protein kinase C-α knockout mice fed a HS diet.32 Thus, effect of TRPV1 on ENaC activity might be associated with activation of phospholipase C/protein kinase C–signaling pathway. Our results indicate that high-salt intake increased SGK1 and WNK1 in mouse CCDs. A compensatory increase in ENaC activity and expression may be attributable to SGK1 and WNK1 upregulation during HS diet. Moreover, dietary capsaicin can inhibit αENaC expression in mice in a TRPV1-dependent manner.
What is the clinical relevance of our study? The reduction of salt intake is essential to prevent hypertension, but changing low-salt consuming habits is not optimal and it is hard to achieve compliance. Chili peppers containing capsaicin are favored and consumed worldwide as vegetables and spices. This study, for the first time, demonstrates that chronic dietary capsaicin can antagonize HS intake–mediated renal sodium reabsorption. Thus, dietary capsaicin may represent a promising lifestyle intervention in populations exposing to a high dietary salt intake.

Perspectives

This study supports the hypothesis that TRPV1 is involved in the regulation of epithelium αENaC function (Figure S5). Dietary capsaicin can ameliorate the jeopardizing effects of a HS diet through activation of TRPV1 in the kidney.

Acknowledgments

We thank Tingbin Cao and Lijuan Wang (Chongqing Institute of Hypertension, China) for technical assistance.

Novelty and Significance

What Is New?

•
Transient receptor potential vanilloid 1 activation by its agonist capsaicin increased urinary sodium excretion through reduced sodium absorption in wild-type mice on a high-salt diet.
•
Long-term dietary capsaicin inhibited the α subunit of epithelial sodium channel and its related with-no-lysine kinase 1/serum- and glucocorticoid-inducible protein kinase 1 pathway in renal cortical collecting ducts and lowered blood pressure in wild-type mice on a high-salt diet.

What Is Relevant?

•
Dietary capsaicin could be a novel nondrug therapeutic strategy for the prevention of high–salt induced hypertension.

Summary

Activation of transient receptor potential vanilloid 1 by chronic dietary capsaicin inhibited α subunit of epithelial sodium channel and reduced α subunit of epithelial sodium channel–mediated sodium reabsorption. Long-term capsaicin treatment lowered blood pressure in mice on a high-salt diet through with-no-lysine kinase 1/serum- and glucocorticoid-inducible protein kinase 1/α subunit of epithelial sodium channel pathway in a transient receptor potential vanilloid 1–dependent manner. Dietary capsaicin may represent a promising lifestyle intervention in populations exposed to a high dietary salt intake.

Supplemental Material

File (hyp_hype201303105_supp1.pdf)

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Published In

Go to Hypertension
Go to Hypertension
Hypertension
Volume 64 • Number 2 • August 2014
Pages: 397 - 404
PubMed: 24890824

Copyright

© 2014 American Heart Association, Inc.

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History

Received: 2 January 2014
Revision received: 23 January 2014
Accepted: 27 April 2014
Published online: 2 June 2014
Published in print: August 2014

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Keywords

  1. capsaicin ENaC alpha
  2. hypertension kidney collecting duct sodium diet transient receptor potential cation channel V1

Subjects

  1. Animal Models of Human Disease
  2. Hypertension
  3. Primary Prevention

Authors

Affiliations

Li Li*
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Fei Wang*
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Xing Wei
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Yi Liang
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Yuanting Cui
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Feng Gao
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Jian Zhong
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Yunfei Pu
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Yu Zhao
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Zhencheng Yan
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
William J. Arendshorst
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Bernd Nilius
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Jing Chen
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Daoyan Liu
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author
Zhiming Zhu
From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China (L.L., F.W., X.W., Y.L., Y.C., F.G., J.Z., Y.P., Y.Z., Z.Y., J.C., D.L., Z.Z.); Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill (W.J.A.); and Department of Cell Molecular Medicine, Laboratory Ion Channel Research, Campus Gasthuisberg, Leuven, Belgium (B.N.).
View all articles by this author

Notes

*
These authors contributed equally to this work.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.114.03105/-/DC1.
Correspondence to Zhiming Zhu or Daoyan Liu, Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Changjiang Zhilu, No. 10, Chongqing 400042, China. E-mail [email protected] or [email protected]

Disclosures

None.

Sources of Funding

This study was funded by the National Basic Research Program of China (2012CB517805, 2013CB531205, and 2011CB503902), the National Natural Science Foundation of China (81370353, 81130006, 91339112, and 91339000), and supported by PCSIRT. The study was funded by the National Institutes of Health (grant number HL-02334) and the grant from the European Foundation for the Study of Diabetes/Chinese Diabetes Society/Lilly Program.

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Transient Receptor Potential Vanilloid 1 Activation by Dietary Capsaicin Promotes Urinary Sodium Excretion by Inhibiting Epithelial Sodium Channel α Subunit–Mediated Sodium Reabsorption
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