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Role of Transient Potential Channels in Cardiovascular and Renal Diseases
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Role of Transient Potential Channels in Cardiovascular and Renal Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 15125

Special Issue Editors

Dr. Michael X. Zhu

E-Mail Website
Guest Editor
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Interests: ion channels; calcium signaling; autophagy; TRP channels; ASICs
Special Issues, Collections and Topics in MDPI journals
Dr. Shuangtao Ma

E-Mail Website
Guest Editor
Michigan State University, East Lansing, MI, USA
Interests: TRP channels; cardiovascular disease; renal injury

Special Issue Information

Dear Colleagues,

Transient receptor potential (TRP) channels are a superfamily of integral membrane proteins that function as cation channels. The TRP superfamily contains the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPP (polycystin), and TRPML (mucolipin) subfamilies. TRP channels are found in a wide range of organisms, from yeast to mammals, and are expressed in both excitable and non-excitable cells. A growing body of evidence indicates that TRP channels are involved in the development of a variety of cardiovascular and renal diseases through various molecular mechanisms. Novel gene-editing technology provides a unique way to reveal the function of TRP channels in the regulation of cardiovascular and renal physiology. High-throughput techniques, including next-generation sequencing and microarrays, along with advanced bioinformatic analyses, provide new insights into the molecular mechanisms for the role of TRP channels in the pathogenesis of cardiovascular and renal diseases. This Special Issue will provide an open-access platform for reviews and original research papers presenting new findings in the TRP channel field, covering a broad range of topics related to the roles of TRP channels in cardiovascular and renal physiology and diseases.

Prof. Dr. Michael X. Zhu
Dr. Shuangtao Ma
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • TRP channels
  • Cardiovascular disease
  • Kidney
  • Hypertension
  • Heart
  • Channelopathy

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

2 pages, 174 KiB  
Editorial
Transient Receptor Potential Channels in Cardiovascular and Renal Diseases
by Shuangtao Ma and Michael X. Zhu
Cells 2022, 11(24), 3960; https://doi.org/10.3390/cells11243960 - 07 Dec 2022
Viewed by 982
Abstract
Transient receptor potential (TRP) channels belong to a superfamily of integral membrane proteins with diverse functions in sensory perception and cellular physiology [...] Full article
(This article belongs to the Special Issue Role of Transient Potential Channels in Cardiovascular and Renal Diseases)

Research

Jump to: Editorial, Review

17 pages, 3718 KiB  
Article
With-No-Lysine Kinase 1 (WNK1) Augments TRPV4 Function in the Aldosterone-Sensitive Distal Nephron
by Viktor N. Tomilin, Kyrylo Pyrshev, Naghmeh Hassanzadeh Khayyat, Oleg Zaika and Oleh Pochynyuk
Cells 2021, 10(6), 1482; https://doi.org/10.3390/cells10061482 - 12 Jun 2021
Cited by 10 | Viewed by 2912
Abstract
Kidneys play a central role in regulation of potassium homeostasis and maintenance of plasma K+ levels within a narrow physiological range. With-no-lysine (WNK) kinases, specifically WNK1 and WNK4, have been recognized to regulate K+ balance, in part, by orchestrating maxi K [...] Read more.
Kidneys play a central role in regulation of potassium homeostasis and maintenance of plasma K+ levels within a narrow physiological range. With-no-lysine (WNK) kinases, specifically WNK1 and WNK4, have been recognized to regulate K+ balance, in part, by orchestrating maxi K+ channel (BK)-dependent K+ secretion in the aldosterone-sensitive distal nephron (ASDN), which includes the connecting tubule and collecting duct. We recently demonstrated that the Ca2+-permeable TRPV4 channel is essential for BK activation in the ASDN. Furthermore, high K+ diet increases TRPV4 activity and expression largely in an aldosterone-dependent manner. In the current study, we aimed to test whether WNK kinases contribute to regulation of TRPV4 activity and its stimulation by aldosterone. Systemic inhibition of WNK with WNK463 (1 mg/kgBW for 3 days) markedly decreased TRPV4-dependent Ca2+ influx in freshly isolated split-opened collecting ducts. Aldosterone greatly increased TRPV4 activity and expression in cultured mpkCCDc14 cells and this effect was abolished in the presence of WNK463. Selective inhibition of WNK1 with WNK-in-11 (400 nM, 24 h) recapitulated the effects of WNK463 on TRPV4-dependent Ca2+ influx. Interestingly, WNK-in-11 did not interfere with up-regulation of TRPV4 expression by aldosterone, but prevented translocation of the channel to the apical plasma membrane. Furthermore, co-expression of TRPV4 and WNK1 into Chinese hamster ovary (CHO) cells increased the macroscopic TRPV4-dependent cation currents. In contrast, over-expression of TRPV4 with a dominant negative WNK1 variant (K233M) decreased the whole-cell currents, suggesting both stimulatory and permissive roles of WNK1 in regulation of TRPV4 activity. Overall, we show that WNK1 is essential for setting functional TRPV4 expression in the ASDN at the baseline and in response to aldosterone. We propose that this new mechanism contributes to regulation of K+ secretion and, by extension, urinary K+ levels to maintain systemic potassium homeostasis. Full article
(This article belongs to the Special Issue Role of Transient Potential Channels in Cardiovascular and Renal Diseases)
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12 pages, 2519 KiB  
Article
Ablation of TRPV1 Abolishes Salicylate-Induced Sympathetic Activity Suppression and Exacerbates Salicylate-Induced Renal Dysfunction in Diet-Induced Obesity
by Beihua Zhong, Shuangtao Ma and Donna H. Wang
Cells 2021, 10(5), 1234; https://doi.org/10.3390/cells10051234 - 18 May 2021
Cited by 5 | Viewed by 2335
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Role of Transient Potential Channels in Cardiovascular and Renal Diseases)
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13 pages, 2333 KiB  
Article
An Arrhythmic Mutation E7K Facilitates TRPM4 Channel Activation via Enhanced PIP2 Interaction
by Yaopeng Hu, Qin Li, Lin-Hai Kurahara, Narumi Shioi, Keizo Hiraishi, Takayuki Fujita, Xin Zhu and Ryuji Inoue
Cells 2021, 10(5), 983; https://doi.org/10.3390/cells10050983 - 22 Apr 2021
Cited by 7 | Viewed by 2332
Abstract
A Ca2+-activated monovalent cation-selective TRPM4 channel is abundantly expressed in the heart. Recently, a single gain-of-function mutation identified in the distal N-terminus of the human TRPM4 channel (Glu5 to Lys5; E7K) was found to be arrhythmogenic because of [...] Read more.
A Ca2+-activated monovalent cation-selective TRPM4 channel is abundantly expressed in the heart. Recently, a single gain-of-function mutation identified in the distal N-terminus of the human TRPM4 channel (Glu5 to Lys5; E7K) was found to be arrhythmogenic because of enhanced cell membrane expression. In this study, we conducted detailed analyses of this mutant channel from more functional aspects, in comparison with its wild type (WT). In an expression system, intracellular application of a short soluble PIP2 (diC8PIP2) restored the single-channel activities of both WT and E7K, which had quickly faded after membrane excision. The potency (Kd) of diC8PIP2 for this recovery was stronger in E7K than its WT (1.44 vs. 2.40 μM). FRET-based PIP2 measurements combined with the Danio rerio voltage-sensing phosphatase (DrVSP) and patch clamping revealed that lowering the endogenous PIP2 level by DrVSP activation reduced the TRPM4 channel activity. This effect was less prominent in E7K than its WT (apparent Kd values estimated from DrVSP-mediated PIP2 depletion: 0.97 and 1.06 μM, respectively), being associated with the differential PIP2-mediated modulation of voltage dependence. Moreover, intracellular perfusion of short N-terminal polypeptides containing either the ‘WT’ or ‘E7K’ sequences respectively attenuated the TRPM4 channel activation at whole-cell and single-channel levels, but in both configurations, the E7K polypeptide exerted greater inhibitory effects. These results collectively suggest that N-terminal interaction with endogenous PIP2 is essential for the TRPM4 channel to function, the extent of which may be abnormally strengthened by the E7K mutation through modulating voltage-dependent activation. The altered PIP2 interaction may account for the arrhythmogenic potential of this mutation. Full article
(This article belongs to the Special Issue Role of Transient Potential Channels in Cardiovascular and Renal Diseases)
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12 pages, 3682 KiB  
Article
Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats
by Eun Young Kim and Stuart E. Dryer
Cells 2021, 10(4), 856; https://doi.org/10.3390/cells10040856 - 09 Apr 2021
Cited by 14 | Viewed by 2050
Abstract
Canonical transient receptor potential 6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS) in patients and animal models, as well as in renal fibrosis following ureteral obstruction in mice. Aging also evokes declines in renal [...] Read more.
Canonical transient receptor potential 6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS) in patients and animal models, as well as in renal fibrosis following ureteral obstruction in mice. Aging also evokes declines in renal function owing to effects on almost every renal compartment in humans and rodents. Here, we have examined the role of TRPC6 in driving inflammation and fibrosis during aging in Sprague-Dawley rats. This was assessed in rats with non-functional TRPC6 channels owing to CRISPR-Cas9 deletion of a portion of the ankyrin repeat domain required for the assembly of functional TRPC6 channels (Trpc6del/del rats). Wild-type littermates (Trpc6wt/wt rats) were used as controls. Animals were evaluated at 2 months and 12 months of age. There was no sign of kidney disease at 2 months of age, regardless of genotype. However, by 12 months of age, all rats examined showed declines in renal function associated with albuminuria, azotemia and increased urine excretion of β2–microglobulin, a marker for proximal tubule pathology. These changes were equally severe in Trpc6wt/wt and Trpc6del/del rats. We also observed age-related increases in renal cortical expression of markers of fibrosis (α-smooth muscle actin and vimentin) and inflammation (NLRP3 and pro-IL−1β), and there was no detectable protective effect of TRPC6 inactivation. Tubulointerstitial fibrosis assessed from histology also appeared equally severe in Trpc6wt/wt and Trpc6del/del rats. By contrast, glomerular pathology, blindly scored from histological sections, suggested a significant protective effect of TRPC6 inactivation, but only within the glomerular compartment. Full article
(This article belongs to the Special Issue Role of Transient Potential Channels in Cardiovascular and Renal Diseases)
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Review

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19 pages, 2706 KiB  
Review
Transient Receptor Potential Channel Ankyrin 1: A Unique Regulator of Vascular Function
by Michael G. Alvarado, Pratish Thakore and Scott Earley
Cells 2021, 10(5), 1167; https://doi.org/10.3390/cells10051167 - 11 May 2021
Cited by 15 | Viewed by 3669
Abstract
TRPA1 (transient receptor potential ankyrin 1), the lone member of the mammalian ankyrin TRP subfamily, is a Ca2+-permeable, non-selective cation channel. TRPA1 channels are localized to the plasma membranes of various cells types, including sensory neurons and vascular endothelial cells. The [...] Read more.
TRPA1 (transient receptor potential ankyrin 1), the lone member of the mammalian ankyrin TRP subfamily, is a Ca2+-permeable, non-selective cation channel. TRPA1 channels are localized to the plasma membranes of various cells types, including sensory neurons and vascular endothelial cells. The channel is endogenously activated by byproducts of reactive oxygen species, such as 4-hydroxy-2-noneal, as well as aromatic, dietary molecules including allyl isothiocyanate, a derivative of mustard oil. Several studies have implicated TRPA1 as a regulator of vascular tone that acts through distinct mechanisms. First, TRPA1 on adventitial sensory nerve fibers mediates neurogenic vasodilation by stimulating the release of the vasodilator, calcitonin gene-related peptide. Second, TRPA1 is expressed in the endothelium of the cerebral vasculature, but not in other vascular beds, and its activation results in localized Ca2+ signals that drive endothelium-dependent vasodilation. Finally, TRPA1 is functionally present on brain capillary endothelial cells, where its activation orchestrates a unique biphasic propagation mechanism that dilates upstream arterioles. This response is vital for neurovascular coupling and functional hyperemia in the brain. This review provides a brief overview of the biophysical and pharmacological properties of TRPA1 and discusses the importance of the channel in vascular control and pathophysiology. Full article
(This article belongs to the Special Issue Role of Transient Potential Channels in Cardiovascular and Renal Diseases)
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