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TRPC6

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https://www.readbyqxmd.com/read/28800680/pharmacological-inhibition-of-fsgs-related-trpc6-gain-of-function-mutants-by-semisynthetic-larixol-derived-compounds
#1
Nicole Urban, Sonja Neuser, Anika Hentschel, Sebastian Köhling, Jörg Rademann, Michael Schaefer
BACKGROUND AND PURPOSE: Gain of function mutations in TRPC6 can cause autosomal dominant forms of focal segmental glomerulosclerosis (FSGS). Validated inhibitors of TRPC6 that are biologically active on FSGS-related TRPC6 mutants are eagerly sought. EXPERIMENTAL APPROACH: We synthesized new TRPC6-inhibiting modulators from larixol, a resiniferous constituent of Larix decidua, and tested the potency and selectivity in cell lines stably expressing various TRP channel isoforms...
August 11, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28790356/trpc6-counteracts-trpc3-nox2-protein-complex-leading-to-attenuation-of-hyperglycemia-induced-heart-failure-in-mice
#2
Sayaka Oda, Takuro Numaga-Tomita, Naoyuki Kitajima, Takashi Toyama, Eri Harada, Tsukasa Shimauchi, Akiyuki Nishimura, Tatsuya Ishikawa, Yoshito Kumagai, Lutz Birnbaumer, Motohiro Nishida
Excess production of reactive oxygen species (ROS) caused by hyperglycemia is a major risk factor for heart failure. We previously reported that transient receptor potential canonical 3 (TRPC3) channel mediates pressure overload-induced maladaptive cardiac fibrosis by forming stably functional complex with NADPH oxidase 2 (Nox2). Although TRPC3 has been long suggested to form hetero-multimer channels with TRPC6 and function as diacylglycerol-activated cation channels coordinately, the role of TRPC6 in heart is still obscure...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28763429/genome-wide-association-study-of-cardiotoxicity-in-the-ncctg-n9831-alliance-adjuvant-trastuzumab-trial
#3
Daniel J Serie, Julia E Crook, Brian M Necela, Travis J Dockter, Xue Wang, Yan W Asmann, DeLisa Fairweather, Katelyn A Bruno, Gerardo Colon-Otero, Edith A Perez, E Aubrey Thompson, Nadine Norton
OBJECTIVES: The major clinical side effect of the ERBB2-targeted breast cancer therapy, trastuzumab, is a decline in the left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity. METHODS: The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or concurrent paclitaxel and trastuzumab (arm C) in patients with HER2-positive breast cancer...
July 31, 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28756533/long-term-spironolactone-treatment-reduces-coronary-trpc-expression-vasoconstriction-and-atherosclerosis-in-metabolic-syndrome-pigs
#4
Wennan Li, Xingjuan Chen, Ashley M Riley, S Christopher Hiett, Constance J Temm, Eleni Beli, Xin Long, Saikat Chakraborty, Mouhamad Alloosh, Fletcher A White, Maria B Grant, Michael Sturek, Alexander G Obukhov
Coronary transient receptor potential canonical (TRPC) channel expression is elevated in metabolic syndrome (MetS). However, differential contribution of TRPCs to coronary pathology in MetS is not fully elucidated. We investigated the roles of TRPC1 and TRPC6 isoforms in coronary arteries of MetS pigs and determined whether long-term treatment with a mineralocorticoid receptor inhibitor, spironolactone, attenuates coronary TRPC expression and associated dysfunctions. MetS coronary arteries exhibited significant atherosclerosis, endothelial dysfunction, and increased histamine-induced contractions...
September 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28751366/recent-advances-in-oxygen-sensing-and-signal-transduction-in-hypoxic-pulmonary-vasoconstriction
#5
Ievgen Strielkov, Oleg Pak, Natascha Sommer, Norbert Weissmann
Hypoxic pulmonary vasoconstriction (HPV) is a physiological reaction, which adapts lung perfusion to regional ventilation and optimizes gas exchange. Impaired HPV may cause systemic hypoxemia, while generalized HPV contributes to the development of pulmonary hypertension. The triggering mechanisms underlying HPV are still not fully elucidated. Several hypotheses are currently under debate, including a possible decrease as well as an increase in reactive oxygen species as a triggering event. Recent findings suggest an increase in the production of reactive oxygen species in pulmonary artery smooth muscle cells by complex III of the mitochondrial electron transport chain and occurrence of oxygen sensing at complex IV...
July 27, 2017: Journal of Applied Physiology
https://www.readbyqxmd.com/read/28747378/nadph-oxidase-nox5-accelerates-renal-injury-in-diabetic-nephropathy
#6
Jay C Jha, Claudine Banal, Jun Okabe, Stephen P Gray, Thushan Hettige, Bryna S M Chow, Vicki Thallas-Bonke, Lisanne De Vos, Chet E Holterman, Melinda T Coughlan, David A Power, Alison Skene, Elif I Ekinci, Mark E Cooper, Rhian M Touyz, Chris R Kennedy, Karin Jandeleit-Dahm
NADPH-oxidase derived excessive production of reactive oxygen species (ROS) in the kidney plays a key role in mediating renal injury in diabetes. Pathological changes in diabetes include mesangial expansion and accumulation of extracellular matrix (ECM) leading to glomerulosclerosis. There is a paucity of data about the role of the Nox5 isoform of NADPH oxidase in animal models of diabetic nephropathy since Nox5 is absent in the mouse genome. Thus, we examined the role of Nox5 in human diabetic nephropathy, in human mesangial cells and in an inducible human Nox5 transgenic mouse exposed to STZ-induced diabetes...
July 26, 2017: Diabetes
https://www.readbyqxmd.com/read/28729555/inhibition-of-phosphodiesterase-5-suppresses-calcineurin-nfat-mediated-trpc6-expression-in-pulmonary-artery-smooth-muscle-cells
#7
Shaojun Li, Yilin Pan, Rui Ke, Xinming Xie, Cui Zhai, Wenhua Shi, Jian Wang, Xin Yan, Limin Chai, Qingting Wang, Qianqian Zhang, Xiaofan Su, Lan Yang, Li Gao, Manxiang Li
The up-regulation of transient receptor potential channel 6 (TRPC6) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMCs), and inhibition of phosphodiesterase-5 (PDE5) has been shown to suppress TRPC6 expression in PASMCs. However, the molecular mechanisms underlying the up-regulation of TRPC6 expression and PDE5 modulation of TRPC6 expression in PASMCs remain largely unclear. The aim of this study is to address these issues. Endothelin-1 (ET-1) dose and time-dependently up-regulated TRPC6 expression in primary cultured rat PASMCs, and this was accompanied with the activation of calcineurin and subsequent translocation of NFATc4 to the nucleus...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28696436/reduced-trpc6-mrna-levels-in-the-blood-cells-of-patients-with-alzheimer-s-disease-and-mild-cognitive-impairment
#8
R Lu, J Wang, R Tao, J Wang, T Zhu, W Guo, Y Sun, H Li, Y Gao, W Zhang, C J Fowler, Q Li, S Chen, Z Wu, C L Masters, C Zhong, N Jing, Y Wang, Y Wang
Transient receptor potential canonical 6 (TRPC6) inhibits β-amyloid (Aβ) production. Hyperforin, the TRPC6 agonist, reduces Aβ levels and improves cognitive performance in Alzheimer's disease (AD) models. However, it's unknown whether TRPC6 expression is changed in AD patients. In this case-control study, we measured TRPC6 expression levels in the peripheral blood cells of four independent AD sets from five hospitals and one mild cognitive impairment (MCI) set from a local community (229 AD, 70 MCI, 40 Parkinson disease and 359 controls from China, total n=698) using quantitative real-time PCR assay...
July 11, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28687864/stressed-podocytes-mechanical-forces-sensors-signaling-and-response
#9
REVIEW
Karlhans Endlich, Felix Kliewe, Nicole Endlich
Increased glomerular capillary pressure (glomerular hypertension) and increased glomerular filtration rate (glomerular hyperfiltration) have been proven to cause glomerulosclerosis in animal models and are likely to be operative in patients. Since podocytes cover the glomerular basement membrane, they are exposed to tensile stress due to circumferential wall tension and to fluid shear stress arising from filtrate flow through the narrow filtration slits and through Bowman's space. In vitro evidence documents that podocytes respond to tensile stress as well as to fluid shear stress...
August 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28672895/role-of-transient-receptor-potential-channel-6-in-the-odontogenic-differentiation-of-human-dental-pulp-cells
#10
Xiaoting Yang, Zhi Song, Lingling Chen, Runfu Wang, Shuheng Huang, Wei Qin, Jia Guo, Zhengmei Lin
Pulp capping is a restorative technique employed in an attempt to maintain pulpal vitality and generate reparative dentin. Ca(2+) released from capping materials is suggested to promote reparative dentin formation. Transient receptor potential channel 6 (TRPC6) is a receptor-operated Ca2+ channel that serves an important role in Ca2+ influx in the majority of non-excitable cells, and influences the calcium signaling and cell respond. Therefore, the purpose of the present study was to gain an insight into the role of TRPC6 in the odontoblastic differentiation of human dental pulp cells (HDPCs)...
July 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28670316/the-role-of-transient-receptor-potential-channel-6-channels-in-the-pulmonary-vasculature
#11
REVIEW
Monika Malczyk, Alexandra Erb, Christine Veith, Hossein Ardeschir Ghofrani, Ralph T Schermuly, Thomas Gudermann, Alexander Dietrich, Norbert Weissmann, Akylbek Sydykov
Canonical or classical transient receptor potential channel 6 (TRPC6) is a Ca(2+)-permeable non-selective cation channel that is widely expressed in the heart, lung, and vascular tissues. The use of TRPC6-deficient ("knockout") mice has provided important insights into the role of TRPC6 in normal physiology and disease states of the pulmonary vasculature. Evidence indicates that TRPC6 is a key regulator of acute hypoxic pulmonary vasoconstriction. Moreover, several studies implicated TRPC6 in the pathogenesis of pulmonary hypertension...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28646178/increased-glomerular-filtration-rate-and-impaired-contractile-function-of-mesangial-cells-in-trpc6-knockout-mice
#12
Weizu Li, Yanfeng Ding, Crystal Smedley, Yanxia Wang, Sarika Chaudhari, Lutz Birnbaumer, Rong Ma
The present study was conducted to determine if TRPC6 regulates glomerular filtration rate (GFR) and the contractile function of glomerular mesangial cells (MCs). GFR was assessed in conscious TRPC6 wild type and knockout mice, and in anesthetized rats with and without in vivo knockdown of TRPC6 in kidneys. We found that GFR was significantly greater, and serum creatinine level was significantly lower in TRPC6 deficient mice. Consistently, local knockdown of TRPC6 in kidney using TRPC6 specific shRNA construct significantly attenuated Ang II-induced GFR decline in rats...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28645743/role-of-trpc3-and-trpc6-channels-in-the-myocardial-response-to-stretch-linking-physiology-and-pathophysiology
#13
REVIEW
Yohei Yamaguchi, Gentaro Iribe, Motohiro Nishida, Keiji Naruse
Transient receptor potential (TRP) channels constitute a large family of versatile multi-signal transducers. In particular, TRP canonical (TRPC) channels are known as receptor-operated, non-selective cation channels. TRPC3 and TRPC6, two members in the TRPC family, are highly expressed in the heart, and participate in the pathogenesis of cardiac hypertrophy and heart failure as a pathological response to chronic mechanical stress. In the pathological response, myocardial stretch increases intracellular Ca(2+) levels and activates nuclear factor of activated T cells to induce cardiac hypertrophy...
June 20, 2017: Progress in Biophysics and Molecular Biology
https://www.readbyqxmd.com/read/28629718/changes-in-podocyte-trpc-channels-evoked-by-plasma-and-sera-from-patients-with-recurrent-fsgs-and-by-putative-glomerular-permeability-factors
#14
Eun Young Kim, Hila Roshanravan, Stuart E Dryer
Primary forms of focal and segmental glomerulosclerosis (FSGS) are driven by circulating factors that cause dysfunction or loss podocytes. Rare genetic forms of FSGS can be caused by mutations in TRPC6, which encodes a Ca(2+)-permeable cationic channel expressed in mesangial cells and podocytes; and NPHS2, which encodes podocin, a TRPC6-binding protein expressed in podocyte slit diaphragm domains. Here we observed that exposing immortalized mouse podocytes to serum or plasma from recurrent FSGS patients for 24h increased the steady-state cell-surface abundance of TRPC6, accompanied by an increase in currents through endogenous TRPC6 channels evoked by a hypoosmotic stretch stimulus...
September 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28627661/altered-expression-of-ppar%C3%A2-%C3%AE-and-trpc-in-neonatal-rats-with-persistent-pulmonary-hypertension
#15
Yanna Du, Jianhua Fu, Li Yao, Lin Qiao, Na Liu, Yujiao Xing, Xindong Xue
Persistent pulmonary hypertension of the newborn (PPHN) is a life‑threatening disease that is commonly observed in the neonatal intensive care unit. PPHN is pathologically characterized by pulmonary vascular remodeling and, in particular, pulmonary artery smooth muscle cell (PASMC) proliferation. Decreased expression levels of peroxisome proliferator‑activated receptor γ (PPAR‑γ), which is a member of the nuclear receptor hormone superfamily, in combination with elevated expressions of transient receptor potential cation channel, subfamily C, member 1 (TRPC1) and TRPC6 contributes to the PASMC proliferation and excessive pulmonary vascular remodeling in adult pulmonary hypertension (PH)...
August 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28596571/the-role-of-trpc6-in-the-neuroprotection-of-calycosin-against-cerebral-ischemic-injury
#16
Chao Guo, Yongyuan Ma, Shanbo Ma, Fei Mu, Jiao Deng, Jialin Duan, Lize Xiong, Ying Yin, Yanhua Wang, Miaomaio Xi, Aidong Wen
Our previous studies have provided evidences that calycosin can protect the brain from ischemia/reperfusion injury, but its mechanisms is not fully understand. Transient receptor potential canonical 6 (TRPC6) has a critical role in promoting neuronal survival against cerebral ischemic injury. The aim of the present study is to test whether calycosin protects against cerebral ischemic injury through TRPC6-CREB pathway. In vivo, rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h and then treated with different doses of calycosin at the onset of reperfusion...
June 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28580132/case-report-making-a-diagnosis-of-familial-renal-disease-clinical-and-patient-perspectives
#17
Zahra Iqbal, John A Sayer
BACKGROUND: A precise molecular genetic diagnosis has become the gold standard for the correct identification and management of many inherited renal diseases. METHODS: Here we describe a family with familial focal segmental glomerulosclerosis, and include a clinical and patient perspective on the diagnostic workup and relaying of genetic results following whole exome sequencing. RESULTS: Through next generation sequencing approaches, we identified a pathogenic mutation in TRPC6, the underlying cause of the phenotype...
2017: F1000Research
https://www.readbyqxmd.com/read/28566634/effect-of-docosahexaenoic-acid-on-voltage-independent-ca-2-entry-pathways-in-cultured-vascular-smooth-muscle-cells-stimulated-with-5-hydroxytryptamine
#18
Takuji Machida, Akina Onoguchi, Kenji Iizuka, Sayuri Ishibashi, Mikiko Yutani, Masahiko Hirafuji
We previously reported that docosahexaenoic acid (DHA) inhibits an increase in intracellular Ca(2+) concentration ([Ca(2+)]i) in cultured rat vascular smooth muscle cells (VSMCs) through a mechanism involving mainly voltage-dependent Ca(2+) channels; however, the effect of DHA on voltage-independent pathways, such as store-operated and receptor-operated Ca(2+) entry, and Ca(2+) entry through Na(+)/Ca(2+) exchanger (NCX), has not been clarified. In the present study, we investigated the effect of DHA treatment on the expression of transient receptor potential canonical (TRPC) channels, capacitative Ca(2+) entry, and Ca(2+) entry through NCX in rat cultured VSMCs stimulated with 5-hydroxytryptamine (5-HT)...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28540409/angiotensin-ii-induces-calcium-calcineurin-signaling-and-podocyte-injury-by-downregulating-microrna-30-family-members
#19
Yue Zhao, Junnan Wu, Mingchao Zhang, Minlin Zhou, Feng Xu, Xiaodong Zhu, Xianguang Zhou, Yue Lang, Fan Yang, Shifeng Yun, Shaolin Shi, Zhihong Liu
Angiotensin II (AngII) is capable of inducing calcium/calcineurin signaling and podocyte injury; however, the precise underlying mechanism is not well understood. Because we have previously demonstrated that microRNA-30s (miR-30s) inhibit calcium/calcineurin signaling in podocytes, we hypothesize that AngII may induce podocyte injury by downregulating miR-30s and thereby activating calcium/calcineurin signaling. To test this hypothesis, we used an AngII-induced podocyte injury mouse model. The mice were treated with AngII via infusion for 28 days, which resulted in hypertension, albuminuria, and glomerular damage...
August 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28531217/store-operated-ca2-entry-supports-contractile-function-in-hearts-of-hibernators
#20
Olga V Nakipova, Alexey S Averin, Edward V Evdokimovskii, Oleg Yu Pimenov, Leonid Kosarski, Dmitriy Ignat'ev, Andrey Anufriev, Yuri M Kokoz, Santiago Reyes, Andre Terzic, Alexey E Alekseev
Hibernators have a distinctive ability to adapt to seasonal changes of body temperature in a range between 37°C and near freezing, exhibiting, among other features, a unique reversibility of cardiac contractility. The adaptation of myocardial contractility in hibernation state relies on alterations of excitation contraction coupling, which becomes less-dependent from extracellular Ca2+ entry and is predominantly controlled by Ca2+ release from sarcoplasmic reticulum, replenished by the Ca2+-ATPase (SERCA)...
2017: PloS One
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