title: Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis.
abstract: Transient receptor potential canonical (TRPC) Ca(2+)-permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II- and 1-oleoyl-2-acetyl-sn-glycerol-induced Ca(2+) entry in these cells, which was detected by fura-2 Ca(2+) imaging. TRPC3 blockade or Ca(2+) removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signal-regulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca(2+) entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca(2+)-mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.
authors.affiliation: Physiology and Pathophysiology Research Laboratory, Pole of Technology and Health, Faculty of Medicine and.
authors.forename: Youakim
authors.initials: Y
authors.lastname: Saliba
authors.affiliation: Physiology and Pathophysiology Research Laboratory, Pole of Technology and Health, Faculty of Medicine and.
authors.forename: Ralph
authors.initials: R
authors.lastname: Karam
authors.affiliation: Faculty of Medicine, Saint Joseph University, Beirut, Lebanon;
authors.forename: Viviane
authors.initials: V
authors.lastname: Smayra
authors.affiliation: Department of Anatomopathology, National Institute of Pathology, Baabda, Lebanon; and.
authors.forename: Georges
authors.initials: G
authors.lastname: Aftimos
authors.affiliation: Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Joel
authors.initials: J
authors.lastname: Abramowitz
authors.affiliation: Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Physiology and Pathophysiology Research Laboratory, Pole of Technology and Health, Faculty of Medicine and nassim.fares@usj.edu.lb.
authors.forename: Nassim
authors.initials: N
authors.lastname: Farès
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005355:Fibrosis; D007668:Kidney / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000166:cytology; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D050052:TRPC Cation Channels / Q000378:metabolism*; D015854:Up-Regulation; D014517:Ureteral Obstruction
chemical_list: D020033:Protein Isoforms; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D002118:Calcium
keywords: calcium; cell; fibroblast; ion channel; kidney disease; renal fibrosis; signaling