title: Alpha1-Adrenergic Receptor Activation Stimulates Calcium Entry and Proliferation via TRPC6 Channels in Cultured Human Mesangial Cells.
abstract: OBJECTIVE
  There is accumulating evidence that sympathetic nervous hyperactivity contributes to the pathogenesis of glomerular sclerosis independent of blood pressure effects. A previous study showed that α1-adrenoceptor (α1-AR) antagonists inhibit mesangial cell (MC) proliferation. However, the underlying mechanism remains unclear.
  
  
  RESULTS
  We found that α1-AR is expressed in a human mesangial cell line. The α1-AR agonist phenylephrine (PE) induced Ca(2+) influx as well as release from intracellular Ca(2+) stores. Blockade of TRPC6 with siRNA, anti-TRPC6 antibodies and a TRPC blocker attenuated the PE-induced [Ca(2+)]i increase. Additionally, the PE-induced [Ca(2+)]i increase was phospholipase C dependent. Furthermore, PE induced a [Ca(2+)]i increase even when the intracellular Ca(2+) stores were already depleted. This effect was mimicked by an analog of diacylglycerol. These results suggested that, upon α1-AR stimulation, TRPC6 mediates Ca(2+) influx via a receptor-operated Ca(2+) entry mechanism. Finally, TRPC6 contributes to the PE-induced MC proliferation. The mechanisms are associated with the extracellular signal-regulated kinase (ERK) signaling pathway because blockade of TRPC6 and chelation of extracellular Ca(2+) abrogated PE-induced ERK1/2 abrogated PE-induced ERK1/2 phosphorylation.
  
  
  CONCLUSIONS
  TRPC6 channels are involved in α1-AR activation-induced Ca(2+) entry, which mediates proliferation via ERK signaling in human MCs.
authors.affiliation: Department of Nephrology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Fanwu
authors.initials: F
authors.lastname: Kong
authors.forename: Linlin
authors.initials: L
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Zou
authors.forename: Kexin
authors.initials: K
authors.lastname: Meng
authors.forename: Tianrong
authors.initials: T
authors.lastname: Ji
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Jundong
authors.initials: J
authors.lastname: Jiao
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport; D020935:MAP Kinase Signaling System; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D050052:TRPC Cation Channels / Q000502:physiology*; D000074287:TRPC6 Cation Channel
chemical_list: D000316:Adrenergic alpha-Agonists; D018340:Receptors, Adrenergic, alpha-1; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D002118:Calcium