scholarly journals Aggravated renal inflammatory responses in TRPV1 gene knockout mice subjected to DOCA-salt hypertension

2009 ◽  
Vol 297 (6) ◽  
pp. F1550-F1559 ◽  
Author(s):  
Youping Wang ◽  
Donna H. Wang
Keyword(s):  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Gene Knockout ◽  
Periodic Acid ◽  
Immunosuppressive Drug ◽  
Transient Receptor Potential Vanilloid ◽  
Tubulointerstitial Injury ◽  
Salt Treatment ◽  
Periodic Acid Schiff ◽  
Salt Hypertension

To test the hypothesis that deletion of the transient receptor potential vanilloid type 1 (TRPV1) channel exaggerates hypertension-induced renal inflammatory response, wild-type (WT) or TRPV1-null mutant (TRPV1−/−) mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for 4 wk. Mean arterial pressure (MAP) determined by radiotelemetry increased in DOCA-salt-treated WT or TRPV1−/− mice, whereas there was no difference in MAP between two strains at the baseline or after DOCA-salt treatment. DOCA-salt treatment increased urinary excretion of albumin and 8-isoprostane in both WT and TRPV1−/− mice, and the increases were greater in magnitude in the latter strain. Periodic acid-Schiff and Mason's trichrome staining showed that kidneys of DOCA-salt-treated TRPV1−/− mice exhibited more severe glomerulosclerosis and tubulointerstitial injury compared with DOCA-salt-treated WT mice. NF-κB assay showed that DOCA-salt treatment increased renal activated NF-κB concentrations in TRPV1−/− mice compared with WT mice. Immunostaining and ELISA assay revealed that DOCA-salt-treated TRPV1−/− mice had enhanced renal infiltration of monocyte/macrophage and lymphocyte, as well as increased renal levels of proinflammatory cytokine (TNF-α, IL-6) and chemokine (MCP-1) compared with DOCA-salt-treated WT mice. Renal ICAM-1 but not VCAM-1 expression was also greater in DOCA-salt-treated TRPV1−/− than WT mice. Dexamethasone (DEXA), an immunosuppressive drug, conveyed a renoprotective effect that was greater in DOCA-salt-treated TRPV1−/− compared with WT mice. These data show that renal inflammation is exacerbated in DOCA-salt hypertension when TRPV1 gene is deleted and that the deterioration is ameliorated by DEXA treatment, indicating that TRPV1 may act as a potential regulator of the inflammatory process to lessen renal injury in DOCA-salt hypertension.

scholarly journals Role of Substance P in Renal Injury During DOCA-Salt Hypertension

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 5972-5979 ◽  
Author(s):  
Youping Wang ◽  
Donna H. Wang
Keyword(s):  
Substance P ◽  
Renal Injury ◽  
Tissue Injury ◽  
Periodic Acid ◽  
Sensory Nerves ◽  
Macrophage Infiltration ◽  
Tubulointerstitial Injury ◽  
Salt Treatment ◽  
Albumin Excretion ◽  
Salt Hypertension

Abstract Substance P (SP), a neurokinin-1 receptor (NK-1R) agonist, is mainly produced and stored in primary sensory nerves and, upon its release, participates in cardiovascular and renal functional regulation. This study tests the hypothesis that activation of the NK-1Rs by SP occurs during hypertension induced by deoxycorticosterone (DOCA)-salt treatment, which contributes to renal injury in this model. C57BL/6 mice were subjected to uninephrectomy and DOCA-salt treatment in the presence or absence of administration of selective NK-1 antagonists, L-733,060 (20 mg/kg·d, ip) or RP-67580 (8 mg/kg·d, ip). Five weeks after the treatment, mean arterial pressure determined by the telemetry system increased in DOCA-salt mice but without difference between NK-1R antagonist-treated or NK-1R antagonist-untreated DOCA-salt groups. Plasma SP levels were increased in DOCA-salt compared with control mice (P < 0.05). Renal hypertrophy and increased urinary 8-isoprostane and albumin excretion were observed in DOCA-salt compared with control mice (P < 0.05). Periodic acid-Schiff and Masson's trichrome staining showed more severe glomerulosclerosis and tubulointerstitial injury in the renal cortex in DOCA-salt compared with control mice, respectively (P < 0.05). Hydroxyproline assay and F4/80-staining showed that renal collagen levels and interstitial monocyte/macrophage infiltration were greater in DOCA-salt compared with control mice, respectively (P < 0.05). Blockade of the NK-1R with L-733,060 or RP-67580 in DOCA-salt mice suppressed increments in urinary 8-isoprostane and albumin excretion, interstitial monocyte/macrophage infiltration, and glomerulosclerosis and tubulointerstitial injury and fibrosis (P < 0.05). Thus, our data show that blockade of the NK-1Rs alleviates renal functional and tissue injury in the absence of alteration in blood pressure in DOCA-salt-hypertensive mice. The results suggest that elevated SP levels during DOCA-salt hypertension play a significant role contributing to renal damage possibly via enhancing oxidative stress and macrophage infiltration of the kidney.

Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell metaplasia

2004 ◽  
Vol 287 (1) ◽  
pp. L127-L133 ◽  
Author(s):  
Je Hyeong Kim ◽  
Sung Yong Lee ◽  
Sang Myeon Bak ◽  
In Bum Suh ◽  
Sang Yeub Lee ◽  
...  
Keyword(s):  
Goblet Cell ◽  
Bacterial Infections ◽  
Inflammatory Responses ◽  
Periodic Acid ◽  
Growth Factor Receptor ◽  
Sprague Dawley ◽  
Neutrophilic Infiltration ◽  
Periodic Acid Schiff ◽  
Mucus Hypersecretion ◽  
Egfr Expression

Bacterial infections of the lung are known to induce inflammatory responses, which lead to mucus hypersecretion. Moreover, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and its activation. Furthermore, matrix metalloproteinases (MMPs), especially MMP-9, have been reported to promote the transmigration of activated neutrophils. In this study, we investigated the associations between lipopolysaccharide (LPS)-induced goblet cell (GC) metaplasia and EGFR expression and the effects of MMP inhibitor (MMPI). Various concentrations of LPS were instilled into the tracheas of pathogen-free Sprague-Dawley rats, and airways were examined at different times after LPS instillation. To examine the role of MMP-9, we treated rats 3 days before LPS instillation and daily thereafter with MMPI. Neutrophilic infiltration, Alcian blue/periodic acid-Schiff (AB/PAS) staining, and immunohistochemical staining for MUC5AC, EGFR, and MMP-9 were performed. The instillation of LPS increased AB/PAS and MUC5AC staining in time- and dose-dependent manners, and treatment with MMPI significantly prevented GC metaplasia. The instillation of LPS into the trachea also induced neutrophilic infiltration and EGFR and MMP-9 expression in the airway epithelium, and MMPI was found to significantly prevent neutrophil recruitment, GC metaplasia, and EGFR and MMP-9 expression. This study demonstrates that the MMP-9 and EGFR cascades are associated with LPS-induced mucus hypersecretion.

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

2020 ◽  
Vol 20 (2) ◽  
pp. 122-130
Author(s):  
Beihua Zhong ◽  
Shuangtao Ma ◽  
Donna H. Wang
Keyword(s):  
Infarct Size ◽  
Transient Receptor Potential ◽  
Diastolic Pressure ◽  
Gene Knockout ◽  
Ischemia Reperfusion ◽  
Control Diet ◽  
Left Ventricular ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channels ◽  
Postischemic Recovery

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. Conclusions: 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.

scholarly journals Adipose-derived exosomes protect the pulmonary endothelial barrier in ventilator-induced lung injury by inhibiting the TRPV4/Ca2+ signaling pathway

2020 ◽  
Vol 318 (4) ◽  
pp. L723-L741 ◽  
Author(s):  
Qian Yu ◽  
Daoxin Wang ◽  
Xiaoting Wen ◽  
Xumao Tang ◽  
Di Qi ◽  
...  
Keyword(s):  
Lung Injury ◽  
Inflammatory Response ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Endothelial Barrier ◽  
Mouse Serum ◽  
Transient Receptor Potential Vanilloid ◽  
Ventilator Induced Lung Injury

Mechanical ventilation (MV) is the main supportive treatment of acute respiratory distress syndrome (ARDS), but it may lead to ventilator-induced lung injury (VILI). Large epidemiological studies have found that obesity was associated with lower mortality in mechanically ventilated patients with acute lung injury, which is known as “obesity paradox.” However, the effects of obesity on VILI are unknown. In the present study, wild-type mice were fed a high-fat diet (HFD) and ventilated with high tidal volume to investigate the effects of obesity on VILI in vivo, and pulmonary microvascular endothelial cells (PMVECs) were subjected to 18% cyclic stretching (CS) to further investigate its underlying mechanism in vitro. We found that HFD protects mice from VILI by alleviating the pulmonary endothelial barrier injury and inflammatory responses in mice. Adipose-derived exosomes can regulate distant tissues as novel adipokines, providing a new mechanism for cell-cell interactions. We extracted three adipose-derived exosomes, including HFD mouse serum exosome (S-Exo), adipose tissue exosome (AT-Exo), and adipose-derived stem cell exosome (ADSC-Exo), and further explored their effects on MV or 18% CS-induced VILI in vivo and in vitro. Administration of three exosomes protected against VILI by suppressing pulmonary endothelial barrier hyperpermeability, repairing the expression of adherens junctions, and alleviating inflammatory response in vivo and in vitro, accompanied by transient receptor potential vanilloid 4 (TRPV4)/Ca2+ pathway inhibition. Collectively, these data indicated that HFD-induced obesity plays a protective role in VILI by alleviating the pulmonary endothelial barrier injury and inflammatory response via adipose-derived exosomes, at least partially, through inhibiting the TRPV4/Ca2+ pathway.

scholarly journals Impairment of the autophagy-lysosomal pathway and activation of pyroptosis in macular corneal dystrophy

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Tao Zheng ◽  
Chuchu Zhao ◽  
Baowen Zhao ◽  
Hanruo Liu ◽  
Shijian Wang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Periodic Acid ◽  
Corneal Transplantation ◽  
Corneal Stroma ◽  
Keratan Sulfate ◽  
Corneal Dystrophy ◽  
Autophagic Flux ◽  
Periodic Acid Schiff ◽  
Caspase 1 ◽  
Macular Corneal Dystrophy

Abstract Macular corneal dystrophy (MCD) is ascribed to mutations in the carbohydrate sulfotransferase (CHST6) gene affecting keratan sulfate (KS) hydrophilicity and causing non-sulfated KS to precipitate in keratocytes and the corneal stroma. We investigated roles for inflammatory responses in MCD pathogenesis by examining the lysosomal-autophagy pathway and activation of pyroptosis in MCD keratocytes. Normal and lesioned keratocytes were obtained from MCD patients undergoing corneal transplantation. The keratocytes were subjected to gene sequencing, RT-PCR, western blotting, transmission electron microscopy, histological staining, induction and inhibition assays of autophagy and pyroptosis, CCK-8 and LysoTracker Green DND-26 labeling, and flow cytometry. A novel homozygous MCD mutation was identified in a family from Northeast China; the mutation was distinguished by cytoplasmic vacuolation, cell membrane disruption, electron dense deposits, and deposition of a band of Periodic acid-Schiff and Alcian blue-positive material in the keratocytes and stroma layer. KS protein levels were decreased, expression of p62 and LC3-II proteins was enhanced, cathepsin D expression was declined and the LysoTracker Green DND-26 signal was dramatically reduced in MCD keratocytes. Bafilomycin-A1 treatment significantly increased caspase-1 and Pro-IL-1β expression in normal and MCD keratocytes. Nod-like receptors pyrins-3 (NLRP3), caspase-1, Pro-IL-1β, and IL-1β levels were pronouncedly elevated in cells exposed to H2O2. Ac-YVAD-CMK treatment reversed this expression in normal and MCD keratocytes. Suppression of the autophagic degradation of non-sulfated KS by impaired autophagic flux in MCD keratocytes triggers pyroptosis. Amelioration of impaired autophagy and restraint of pyroptosis may, therefore, have therapeutic efficacy in the treatment of MCD.

scholarly journals Nax signaling evoked by an increase in [Na+] in CSF induces water intake via EET-mediated TRPV4 activation

2016 ◽  
Vol 311 (2) ◽  
pp. R299-R306 ◽  
Author(s):  
Hiraki Sakuta ◽  
Eri Nishihara ◽  
Takeshi Y. Hiyama ◽  
Chia-Hao Lin ◽  
Masaharu Noda
Keyword(s):  
Water Intake ◽  
Transient Receptor Potential ◽  
Gene Knockout ◽  
Receptor Potential ◽  
Circumventricular Organs ◽  
Transient Receptor Potential Vanilloid ◽  
Intracerebroventricular Injection ◽  
Level Sensor ◽  
Underlying Mechanisms ◽  
The Brain

Water-intake behavior is under the control of brain systems that sense body fluid conditions at sensory circumventricular organs (sCVOs); however, the underlying mechanisms have not yet been elucidated in detail. Nax is a sodium (Na+) level sensor in the brain, and the transient receptor potential vanilloid (TRPV) channels TRPV1 and TRPV4 have been proposed to function as osmosensors. We herein investigated voluntary water intake immediately induced after an intracerebroventricular administration of a hypertonic NaCl solution in TRPV1-, TRPV4-, Na x-, and their double-gene knockout (KO) mice. The induction of water intake by TRPV1-KO mice was normal, whereas intake by TRPV4-KO and Na x-KO mice was significantly less than that by WT mice. Water intake by Na x /TRPV4-double KO mice was similar to that by the respective single KO mice. When TRPV4 activity was blocked with a specific antagonist HC-067047, water intake by WT mice was significantly reduced, whereas intake by TRPV4-KO and Na x-KO mice was not. Similar results were obtained with the administration of miconazole, which inhibits the biosynthesis of epoxyeicosatrienoic acids (EETs), endogenous agonists for TRPV4, from arachidonic acid (AA). Intracerebroventricular injection of hypertonic NaCl with AA or 5,6-EET restored water intake by Na x-KO mice to the wild-type level but not that by TRPV4-KO mice. These results suggest that the Na+ signal generated in Nax-positive glial cells leads to the activation of TRPV4-positive neurons in sCVOs to stimulate water intake by using EETs as gliotransmitters. Intracerebroventricular injection of equiosmolar hypertonic sorbitol solution induced small but significant water intake equally in all the genotypes, suggesting the presence of an unknown osmosensor in the brain.

scholarly journals Activation of transient receptor potential vanilloid 4 protects articular cartilage against IL-1β-induced inflammatory responses by regulating the CaMKK/AMPK/NF-κB signaling pathway

2021 ◽  
Author(s):  
Kyosuke Hattori ◽  
Nobunori Takahashi ◽  
Kenya Terabe ◽  
Yoshifumi Ohashi ◽  
Kenji Kishimoto ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Protein Kinase ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Receptor Potential ◽  
Cartilage Tissue ◽  
Transient Receptor Potential Vanilloid ◽  
Compound C ◽  
Transient Receptor ◽  
Safranin O

Abstract Transient receptor potential vanilloid 4 (TRPV4) plays an important role in chondrocytes via Ca2+ signaling. However, its role in the progression of osteoarthritis is unclear. This study aimed to evaluate the effects of TRPV4 activation on articular cartilage and chondrocytes stimulated with interleukin (IL)-1β. Bovine and human articular chondrocytes were stimulated with various agents, including IL-1β, GSK1016790A (GSK101; a TRPV4 agonist), Compound C (an AMP-activated protein kinase (AMPK) inhibitor), and STO-609 (a calmodulin-dependent protein kinase kinase (CaMKK) inhibitor), and were processed for Western blot analysis and real-time PCR. The dimethylmethylene blue (DMMB) assay and Safranin O staining were also performed. GSK101 reversed the IL-1β-induced increase in expression of matrix metalloproteinase (MMP)-13 and decrease in expression of aggrecan. GSK101 also decreased proteoglycan release in the DMMB assay and retained Safranin O staining of articular cartilage tissue. Furthermore, GSK101 increased AMPK phosphorylation and decreased IL-1β-induced nuclear factor kappa B (NF-κB) phosphorylation. Compound C and STO-609 reversed the suppressive effects of GSK101 on NF-κB activation and MMP-13 expression. In conclusion, TRPV4 activation had chondroprotective effects on articular cartilage stimulated with IL-1β by activating CaMKK/AMPK and suppressing the NF-κB pathway. TRPV activators may offer a promising therapeutic option for preventing the progression of osteoarthritis.

scholarly journals Negative Cellular Effects of Urban Particulate Matter on Human Keratinocytes Are Mediated by P38 MAPK and NF-κB-dependent Expression of TRPV 1

2018 ◽  
Vol 19 (9) ◽  
pp. 2660 ◽  
Author(s):  
Kitae Kwon ◽  
See-Hyoung Park ◽  
Byung Han ◽  
Sae Oh ◽  
Seung Lee ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Receptor Potential ◽  
Human Keratinocytes ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Transient Receptor Potential Vanilloid ◽  
Urban Particulate Matter

Urban particulate matter (UPM) exerts negative effects on various human organs. Transient receptor potential vanilloid 1 (TRPV1) is a polymodal sensory transducer that can be activated by multiple noxious stimuli. This study aimed to explore the effects of the UPM 1648a on the expression of TRPV1, and its regulatory mechanisms in HaCaT cells. UPM enhanced TRPV 1 promoter-luciferase reporter activity. UPM also increased expression of the TRPV 1 gene as evidenced by increased mRNA and protein levels of TRPV 1. In addition, elucidation of the underlying mechanism behind the UPM-mediated effects on TRPV 1 expression revealed that UPM can upregulate expression of the TRPV1 gene by activating activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB). The UPM treatment also altered Ca2+ influx and cell proliferation, as well as production of interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). In addition, these UPM-induced effects were attenuated by SB203580 and ammonium pyrrolidinedithiocarbamate (PDTC). However, SP600125 and PD98059 did not alter the UPM-induced effects. Taken together, these findings indicate that UPM upregulates expression of the TRPV 1 gene, which is mediated by the p38 mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways and suggest that UPM is a potential irritant that can induce skin processes such as aging and inflammatory responses.

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