title: Receptor channel TRPC6 orchestrate the activation of human hepatic stellate cell under hypoxia condition.
abstract: Hepatic stellate cells (HSCs), a specialized stromal cytotype have a great impact on the biological behaviors of liver diseases. Despite this fact, the underlying mechanism that regulates HSC still remains poorly understood. The aim of the present study was to understand the role of TRPC6 signaling in regulating the molecular mechanism of HSCs in response to hypoxia. In the present study we showed that under hypoxia condition, the upregulated Hypoxia Inducible Factor 1α (HIF1α) increases NICD activation, which in turn induces the expression of transient receptor potential channel 6 (TRPC6) in HSC line lx-2. TRPC6 causes a sustained elevation of intracellular calcium which is coupled with the activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway which activates the synthesis of extracellular matrix proteins. TRPC6 also activates SMAD2/3 dependent TGF-β signaling in facilitating upregulated expression of αSMA and collagen. As activated HSCs may be a suitable target for HCC therapy and targeting these cells rather than the HCC cells may result in a greater response. Collectively, our studies indicate for the first time the detailed mechanism of activation of HSC through TRPC6 signaling and thus being a promising therapeutic target.
authors.affiliation: Unit of Biochemistry, Department of Zoology, School of Life Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India. Electronic address: chidambaram.soumya@gmail.com.
authors.forename: Soumya C
authors.initials: SC
authors.lastname: Iyer
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India.
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Kannan
authors.affiliation: Unit of Biochemistry, Department of Zoology, School of Life Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India.
authors.forename: Ashidha
authors.initials: A
authors.lastname: Gopal
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India.
authors.forename: Niranjali
authors.initials: N
authors.lastname: Devaraj
authors.affiliation: Unit of Biochemistry, Department of Zoology, School of Life Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India.
authors.forename: Devaraj
authors.initials: D
authors.lastname: Halagowder
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051880:Receptors, Notch; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human
keywords: Hepatic stellate cells; Hypoxia; NICD; TRPC6