title: Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho.
abstract: Fibrosis is an exaggerated form of tissue repair that occurs with serious damage or repetitive injury and ultimately leads to organ failure due to the excessive scarring. Increased calcium ion entry through the TRPC6 channel has been associated with the pathogenesis of heart and glomerular diseases, but its role in renal interstitial fibrosis is unknown. We studied this by deletion of Trpc6 in mice and found it decreased unilateral ureteral obstruction-induced interstitial fibrosis and blunted increased mRNA expression of fibrosis-related genes in the ureteral obstructed kidney relative to that in the kidney of wild-type mice. Administration of BTP2, a pyrazol derivative known to inhibit function of several TRPC channels, also ameliorated obstruction-induced renal fibrosis and gene expression in wild-type mice. BTP2 inhibited carbachol-activated TRPC3 and TRPC6 channel activities in HEK293 cells. Ureteral obstruction caused over a 10-fold increase in mRNA expression for TRPC3 as well as TRPC6 in the kidneys of obstructed relative to the sham-operated mice. The magnitude of protection against obstruction-induced fibrosis in Trpc3 and Trpc6 double knockout mice was not different from that in Trpc6 knockout mice. Klotho, a membrane and soluble protein predominantly produced in the kidney, is known to confer protection against renal fibrosis. Administration of soluble klotho significantly reduced obstruction-induced renal fibrosis in wild-type mice, but not in Trpc6 knockout mice, indicating that klotho and TRPC6 inhibition act in the same pathway to protect against obstruction-induced renal fibrosis. Thus klotho and TRPC6 may be pharmacologic targets for treating renal fibrosis.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yueh-Lin
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.affiliation: Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Sung-Wan
authors.initials: SW
authors.lastname: An
authors.affiliation: CardioMetabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
authors.forename: Noelynn
authors.initials: N
authors.lastname: Oliver
authors.affiliation: CardioMetabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
authors.forename: Nestor X
authors.initials: NX
authors.lastname: Barrezueta
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Mei-Hsiang
authors.initials: MH
authors.lastname: Lin
authors.affiliation: Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Institute of Biomedical Research (BIOMED), Catholic University of Argentina, Buenos Aires, Argentina.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address: Chou-Long.Huang@UTSouthwestern.edu.
authors.forename: Chou-Long
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005966:Glucuronidase / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000090265:Klotho Proteins; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger; D015398:Signal Transduction / Q000187:drug effects; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D013830:Thiadiazoles / Q000494:pharmacology*; D014162:Transfection; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064804:Urological Agents / Q000494:pharmacology*
chemical_list: C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D012333:RNA, Messenger; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; D013830:Thiadiazoles; C492146:Trpc6 protein, mouse; D064804:Urological Agents; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: BTP2; TRPC3; TRPC6; UUO; fibrosis; klotho