scholarly journals TRPV1 Hyperfunction Contributes to Renal Inflammation in Oxalate Nephropathy

2021 ◽  
Vol 22 (12) ◽  
pp. 6204
Author(s):  
Chien-Lin Lu ◽  
Te-Yi Teng ◽  
Min-Tser Liao ◽  
Ming-Chieh Ma
Keyword(s):  
Oxidative Stress ◽  
Transient Receptor Potential ◽  
Cell Damage ◽  
Transient Receptor Potential Vanilloid ◽  
Tubular Damage ◽  
Dependent Manner ◽  
Crystal Deposition ◽  
Renal Inflammation ◽  
Urinary Supersaturation ◽  
Oxalate Nephropathy

Inflammation worsens oxalate nephropathy by exacerbating tubular damage. The transient receptor potential vanilloid 1 (TRPV1) channel is present in kidney and has a polymodal sensing ability. Here, we tested whether TRPV1 plays a role in hyperoxaluria-induced renal inflammation. In TRPV1-expressed proximal tubular cells LLC-PK1, oxalate could induce cell damage in a time- and dose-dependent manner; this was associated with increased arachidonate 12-lipoxygenase (ALOX12) expression and synthesis of endovanilloid 12(S)-hydroxyeicosatetraenoic acid for TRPV1 activation. Inhibition of ALOX12 or TRPV1 attenuated oxalate-mediated cell damage. We further showed that increases in intracellular Ca2+ and protein kinase C α activation are downstream of TRPV1 for NADPH oxidase 4 upregulation and reactive oxygen species formation. These trigger tubular cell inflammation via increased NLR family pyrin domain-containing 3 expression, caspase-1 activation, and interleukin (IL)-1β release, and were alleviated by TRPV1 inhibition. Male hyperoxaluric rats demonstrated urinary supersaturation, tubular damage, and oxidative stress in a time-dependent manner. Chronic TRPV1 inhibition did not affect hyperoxaluria and urinary supersaturation, but markedly reduced tubular damage and calcium oxalate crystal deposition by lowering oxidative stress and inflammatory signaling. Taking all these results together, we conclude that TRPV1 hyperfunction contributes to oxalate-induced renal inflammation. Blunting TRPV1 function attenuates hyperoxaluric nephropathy.

scholarly journals TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage

2020 ◽  
Vol 21 (17) ◽  
pp. 6212 ◽  
Author(s):  
Chien-Lin Lu ◽  
Chun-Hou Liao ◽  
Kuo-Cheng Lu ◽  
Ming-Chieh Ma
Keyword(s):  
Transient Receptor Potential ◽  
Mdck Cells ◽  
Indoxyl Sulfate ◽  
Transient Receptor Potential Vanilloid ◽  
Tubular Damage ◽  
Uremic Toxin ◽  
Dependent Manner ◽  
Renal Tubular Damage ◽  
Tubular Cells ◽  
Renal Tubular

Indoxyl sulfate (IS) is accumulated during severe renal insufficiency and known for its nephrotoxic properties. Transient receptor potential vanilloid 1 (TRPV1) is present in the kidney and acts as a renal sensor. However, the mechanism underlying IS-mediated renal tubular damage in view of TRPV1 is lacking. Here, we demonstrated that TRPV1 was expressed in tubular cells of Lilly Laboratories cell-porcine kidney 1 (LLC-PK1) and Madin-Darby canine kidney cells (MDCK). IS treatment in both cells exhibited tubular damage with increased LDH release and reduced cell viability in dose- and time-dependent manners. MDCK, however, was more vulnerable to IS. We, therefore, investigated MDCK cells to explore a more detailed mechanism. Interestingly, IS-induced tubular damage was markedly attenuated in the presence of selective TRPV1 blockers. IS showed no effect on TRPV1 expression but significantly increased arachidonate 12-lipoxygenase (ALOX12) protein, mRNA expression, and 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) amounts in a dose-dependent manner, indicating that the ALOX12/12(S)-HETE pathway induced TRPV1 hyperfunction in IS-mediated tubulotoxicity. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-α-cyanocinnamate or baicalein attenuated the effects of IS. Since aryl hydrocarbon receptor (AhR) activation after IS binding is crucial in mediating cell death, here, we found that the AhR blockade not only ameliorated tubular damage but also attenuated ALOX12 expression and 12(S)-HETE production caused by IS. The uremic toxic adsorbent AST-120, however, showed little effect on ALOX12 and 12(S)-HETE, as well as IS-induced cell damage. These results clearly indicated that IS activated AhR and then upregulated ALOX12, and this induced endovanilloid 12(S)-HETE synthesis and contributed to TRPV1 hyperfunction in IS-treated tubular cells. Further study on TRPV1 may attenuate kidney susceptibility to the functional loss of end-stage kidney disease via IS.

scholarly journals Modulation of the Oxidative Stress and Lipid Peroxidation by Endocannabinoids and Their Lipid Analogues

Antioxidants ◽  
2018 ◽  
Vol 7 (7) ◽  
pp. 93 ◽  
Author(s):  
Cristina Gallelli ◽  
Silvio Calcagnini ◽  
Adele Romano ◽  
Justyna Koczwara ◽  
Marialuisa de Ceglia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Tissue Injury ◽  
Cell Damage ◽  
Transient Receptor Potential Vanilloid ◽  
Peroxisome Proliferator ◽  
Enzymatic Antioxidants ◽  
Reactive Aldehydes

Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes. In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein-coupled receptors 18 and 55. Moreover, the endocannabinoids lipid analogues N-acylethanolamines showed to protect cell damage and death from reactive aldehydes-induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts.

scholarly journals Inhibition of Microglia-Derived Oxidative Stress by Ciliary Neurotrophic Factor Protects Dopamine Neurons In Vivo from MPP+ Neurotoxicity

2018 ◽  
Vol 19 (11) ◽  
pp. 3543 ◽  
Author(s):  
Jeong Baek ◽  
Jae Jeong ◽  
Kyoung Kim ◽  
So-Yoon Won ◽  
Young Chung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurotrophic Factor ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Ciliary Neurotrophic Factor ◽  
Dopamine Neurons ◽  
Transient Receptor Potential Vanilloid

We demonstrated that capsaicin (CAP), an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), inhibits microglia activation and microglia-derived oxidative stress in the substantia nigra (SN) of MPP+-lesioned rat. However, the detailed mechanisms how microglia-derived oxidative stress is regulated by CAP remain to be determined. Here we report that ciliary neurotrophic factor (CNTF) endogenously produced by CAP-activated astrocytes through TRPV1, but not microglia, inhibits microglial activation and microglia-derived oxidative stress, as assessed by OX-6 and OX-42 immunostaining and hydroethidine staining, respectively, resulting in neuroprotection. The significant increase in levels of CNTF receptor alpha (CNTFRα) expression was evident on microglia in the MPP+-lesioned rat SN and the observed beneficial effects of CNTF was abolished by treatment with CNTF receptor neutralizing antibody. It is therefore likely that CNTF can exert its effect via CNTFRα on microglia, which rescues dopamine neurons in the SN of MPP+-lesioned rats and ameliorates amphetamine-induced rotations. Immunohistochemical analysis revealed also a significantly increased expression of CNTFRα on microglia in the SN from human Parkinson’s disease patients compared with age-matched controls, indicating that these findings may have relevance to the disease. These data suggest that CNTF originated from TRPV1 activated astrocytes may be beneficial to treat neurodegenerative disease associated with neuro-inflammation such as Parkinson’s disease.

scholarly journals Bladder Dysfunction in an Obese Zucker Rat: The Role of TRPA1 Channels, Oxidative Stress, and Hydrogen Sulfide

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Igor Blaha ◽  
María Elvira López-Oliva ◽  
María Pilar Martínez ◽  
Paz Recio ◽  
Ángel Agis-Torres ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Sulfide ◽  
Transient Receptor Potential ◽  
Bladder Dysfunction ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Antioxidant Enzyme Activities ◽  
Zucker Rat ◽  
Obese Zucker Rat ◽  
Transient Receptor

Purpose. This study investigates whether functionality and/or expression changes of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) channels, oxidative stress, and hydrogen sulfide (H2S) are involved in the bladder dysfunction from an insulin-resistant obese Zucker rat (OZR). Materials and Methods. Detrusor smooth muscle (DSM) samples from the OZR and their respective controls, a lean Zucker rat (LZR), were processed for immunohistochemistry for studying the expression of TRPA1 and TRPV1 and the H2S synthase cystathionine beta-synthase (CBS) and cysthathionine-γ-lyase (CSE). Isometric force recordings to assess the effects of TRPA1 agonists and antagonists on DSM contractility and measurement of oxidative stress and H2S production were also performed. Results. Neuronal TRPA1 expression was increased in the OZR bladder. Electrical field stimulation- (EFS-) elicited contraction was reduced in the OZR bladder. In both LZR and OZR, TRPA1 activation failed to modify DSM basal tension but enhanced EFS contraction; this response is inhibited by the TRPA1 blockade. In the OZR bladder, reactive oxygen species, malondialdehyde, and protein carbonyl contents were increased and antioxidant enzyme activities (superoxide dismutase, catalase, GR, and GPx) were diminished. CSE expression and CSE-generated H2S production were also reduced in the OZR. Both TRPV1 and CBS expressions were not changed in the OZR. Conclusions. These results suggest that an increased expression and functionality of TRPA1, an augmented oxidative stress, and a downregulation of the CSE/H2S pathway are involved in the impairment of nerve-evoked DSM contraction from the OZR.

scholarly journals Inhibitory Effect of Manassantin B Isolated from Saururus chinensis on Skin Heat Aging

Cosmetics ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. 47
Author(s):  
Hwa Sun Ryu ◽  
Jeong-Yeon Choi ◽  
Kyeong-Sun Lee ◽  
Jung-No Lee ◽  
Chun Mong Lee ◽  
...  
Keyword(s):  
Heat Shock ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Skin Aging ◽  
Shock Treatment ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Heat Shock Treatment ◽  
Channel Inhibition ◽  
Saururus Chinensis

Heat shock treatment-induced skin aging causes a thickened epidermis, increased matrix metalloproteinase (MMP)-1 expression, collagen degradation, and deep wrinkles. In this study, we investigated the effect of manassantin B in preventing heat shock treatment-induced aging. We first separated manassantin B (MB) from the roots of Saururus chinensis, and the structure was identified using 1H- and 13C-NMR spectroscopy. RT-PCR and western blotting were applied to investigate the anti-aging effect of manassantin B. Manassantin B decreased MMP-1 expression through transient receptor potential vanilloid (TRPV) 1 channel inhibition and significantly increased procollagen expression. In addition, manassantin B suppressed MAPK phosphorylation in a dose-dependent manner. Our results suggest that manassantin B, the active ingredient in S. chinensis, can be effectively used to inhibit heat shock treatment-induced skin aging.

Hydrogen sulfide modulates IL-6/STAT3 pathway and inhibits oxidative stress, inflammation, and apoptosis in rat model of methotrexate hepatotoxicity

2019 ◽  
Vol 39 (1) ◽  
pp. 77-85 ◽  
Author(s):  
AA Fouad ◽  
HM Hafez ◽  
AAH Hamouda
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Sulfide ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Nuclear Factor Κb ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
Stat3 Pathway ◽  
Anti Inflammatory ◽  
Apoptotic Effects

Methotrexate (MTX) is a commonly used anticancer and immunosuppressive agent. However, MTX can induce hepatotoxicity due to oxidative stress, inflammation, and apoptosis. Hydrogen sulfide (H2S), the endogenous gaseous molecule, has antioxidant, anti-inflammatory, and anti-apoptotic effects. The present work explored the probable protective effect of H2S against MTX hepatotoxicity in rats and also the possible mechanisms underlying this effect. MTX was given at a single intraperitoneal (i.p.) dose of 20 mg/kg. Sodium H2S (56 µmol /kg/day, i.p.), as H2S donor, was given for 10 days, starting 6 days before MTX administration. H2S significantly reduced serum alanine aminotransferase, hepatic malondialdehyde, interleukin 6, nuclear factor κB p65, cytosolic cytochrome c, phosphorylated signal transducer and activator of transcription 3, and Bax/Bcl-2 ratio and significantly increased hepatic total antioxidant capacity and endothelial nitric oxide synthase (eNOS) in rats received MTX. In addition, H2S minimized the histopathological injury and significantly decreased the expression of STAT3 in liver tissue of MTX-challenged rats. The effects of H2S were significantly antagonized by administration of glibenclamide as KATP channel blocker, Nω-nitro-l-arginine, as eNOS inhibitor, or ruthenium red, as transient receptor potential vanilloid 1 (TRPV1) antagonist. It was concluded that H2S provided significant hepatoprotection in MTX-challenged rats through its antioxidant, anti-inflammatory, anti-apoptotic effects. These effects are most probably mediated by the ability of H2S to act as IL-6/STAT3 pathway modulator, KATP channel opener, eNOS activator, and TRPV1 agonist.

Oxidative stress-induced posttranslational modification of TRPV1 expressed in esophageal epithelial cells

2011 ◽  
Vol 301 (2) ◽  
pp. G230-G238 ◽  
Author(s):  
Etsuko Kishimoto ◽  
Yuji Naito ◽  
Osamu Handa ◽  
Hitomi Okada ◽  
Katsura Mizushima ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Posttranslational Modification ◽  
Transient Receptor Potential ◽  
Epithelial Cell Line ◽  
Transient Receptor Potential Vanilloid ◽  
Esophageal Mucosa ◽  
Chemokine Production ◽  
Modified Proteins ◽  
Esophageal Epithelial Cells

Human esophageal epithelium is continuously exposed to physical stimuli or to gastric acid that sometimes causes inflammation of the mucosa. Transient receptor potential vanilloid 1 (TRPV1) is a nociceptive, Ca2+-selective ion channel activated by capsaicin, heat, and protons. It has been reported that activation of TRPV1 expressed in esophageal mucosa is involved in gastroesophageal reflux disease (GERD) or in nonerosive GERD symptoms. In this study, we examined the expression and function of TRPV1 in the human esophageal epithelial cell line Het1A, focusing in particular on the role of oxidative stress. Interleukin-8 (IL-8) secreted by Het1A cells upon stimulation by capsaicin or acid with/without 4-hydroxy-2-nonenal (HNE) was measured by ELISA. Following capsaicin stimulation, the intracellular production of reactive oxygen species (ROS) was determined using a redox-sensitive fluorogenic probe, and ROS- and HNE-modified proteins were determined by Western blotting using biotinylated cysteine and anti-HNE antibody, respectively. HNE modification of TRPV1 proteins was further investigated by immunoprecipitation after treatment with synthetic HNE. Capsaicin and acid induced IL-8 production in Het1A cells, and this production was diminished by antagonists of TRPV1. Capsaicin also significantly increased the production of intracellular ROS and ROS- or HNE-modified proteins in Het1A cells. Moreover, IL-8 production in capsaicin-stimulated Het1A cells was enhanced by synthetic HNE treatment. Immunoprecipitation studies revealed that TRPV1 was modified by HNE in synthetic HNE-stimulated Het1A cells. We concluded that TRPV1 functions in chemokine production in esophageal epithelial cells, and this function may be regulated by ROS via posttranslational modification of TRPV1.

scholarly journals The nonselective cation channel TRPV4 inhibits angiotensin II receptors

2020 ◽  
Vol 295 (29) ◽  
pp. 9986-9997
Author(s):  
Nicholas W. Zaccor ◽  
Charlotte J. Sumner ◽  
Solomon H. Snyder
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Trp Channel ◽  
Luciferase Assay ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Transient Receptor

G-protein–coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of β-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a β-arrestin–dependent luciferase assay, we characterize a GPCR–TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits β-arrestin–dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II–mediated G-protein–associated second messenger accumulation, AT1R receptor phosphorylation, and β-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin–dependent manner, preventing β-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.

scholarly journals TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation

2017 ◽  
Vol 312 (5) ◽  
pp. C562-C572 ◽  
Author(s):  
Shweta Sharma ◽  
Rishov Goswami ◽  
Michael Merth ◽  
Jonathan Cohen ◽  
Kai Y. Lei ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Dermal Fibroblasts ◽  
Transient Receptor Potential Vanilloid ◽  
Myofibroblast Differentiation ◽  
Dependent Manner ◽  
Matrix Stiffness ◽  
Functional Link ◽  
Genetic Ablation

Scleroderma is a multisystem fibroproliferative disease with no effective medical treatment. Myofibroblasts are critical to the fibrogenic tissue repair process in the skin and many internal organs. Emerging data support a role for both matrix stiffness, and transforming growth factor β1 (TGFβ1), in myofibroblast differentiation. Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel activated by both mechanical and biochemical stimuli. The objective of this study was to determine the role of TRPV4 in TGFβ1- and matrix stiffness-induced differentiation of dermal fibroblasts. We found that TRPV4 channels are expressed and functional in both human (HDF) and mouse (MDF) dermal fibroblasts. TRPV4 activity (agonist-induced Ca2+ influx) was induced by both matrix stiffness and TGFβ1 in dermal fibroblasts. TGFβ1 induced expression of TRPV4 proteins in a dose-dependent manner. Genetic ablation or pharmacological antagonism of TRPV4 channel abrogated Ca2+ influx and both TGFβ1-induced and matrix stiffness-induced myofibroblast differentiation as assessed by 1) α-smooth muscle actin expression/incorporation into stress fibers, 2) generation of polymerized actin, and 3) expression of collagen-1. We found that TRPV4 inhibition abrogated TGFβ1-induced activation of AKT but not of Smad2/3, suggesting that the mechanism by which profibrotic TGFβ1 signaling in dermal fibroblasts is modified by TRPV4 may be through non-Smad pathways. Altogether, these data identify a novel reciprocal functional link between TRPV4 activation and TGFβ1 signals regulating dermal myofibroblast differentiation. These findings suggest that therapeutic inhibition of TRPV4 activity may provide a targeted approach to the treatment of scleroderma.

scholarly journals PRMT1 and PRMT4 Regulate Oxidative Stress-Induced Retinal Pigment Epithelial Cell Damage in SIRT1-Dependent and SIRT1-Independent Manners

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Dong-Il Kim ◽  
Min-Jung Park ◽  
Joo-Hee Choi ◽  
In-Seon Kim ◽  
Ho-Jae Han ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Retinopathy ◽  
Retinal Pigment Epithelial ◽  
Cell Damage ◽  
Retinal Pigment ◽  
Arginine Methylation ◽  
Type I ◽  
Dependent Manner ◽  
Sirt1 Expression ◽  
Pigment Epithelial

Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is involved in the progression of diabetic retinopathy. Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) has emerged as an important histone modification involved in diverse diseases. Sirtuin (SIRT1) is a protein deacetylase implicated in the onset of metabolic diseases. Therefore, we examined the roles of type I PRMTs and their relationship with SIRT1 in human RPE cells under H2O2-induced oxidative stress. H2O2treatment increased PRMT1 and PRMT4 expression but decreased SIRT1 expression. Similar to H2O2treatment, PRMT1 or PRMT4 overexpression increased RPE cell damage. Moreover, the H2O2-induced RPE cell damage was attenuated by PRMT1 or PRMT4 knockdown and SIRT1 overexpression. In this study, we revealed that SIRT1 expression was regulated by PRMT1 but not by PRMT4. Finally, we found that PRMT1 and PRMT4 expression is increased in the RPE layer of streptozotocin-treated rats. Taken together, we demonstrated that oxidative stress induces apoptosis both via PRMT1 in a SIRT1-dependent manner and via PRMT4 in a SIRT1-independent manner. The inhibition of the expression of type I PRMTs, especially PRMT1 and PRMT4, and increased SIRT1 could be therapeutic approaches for diabetic retinopathy.

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