title: TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.
abstract: Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.
authors.affiliation: Renal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA. jreiser@partners.org
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Polu
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Möller
authors.forename: Peter
authors.initials: P
authors.lastname: Kenlan
authors.forename: Mehmet M
authors.initials: MM
authors.lastname: Altintas
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.forename: Stephanie
authors.initials: S
authors.lastname: Herbert
authors.forename: Ivan
authors.initials: I
authors.lastname: Villegas
authors.forename: Carmen
authors.initials: C
authors.lastname: Avila-Casado
authors.forename: Mary
authors.initials: M
authors.lastname: McGee
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
authors.forename: Paula L
authors.initials: PL
authors.lastname: Smith
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: D000293:Adolescent; D000328:Adult; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel
chemical_list: D015220:Calcium Channels; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human