TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.
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.
Reiser
Jochen
J
Renal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA. jreiser@partners.org
Polu
Krishna R
KR
Möller
Clemens C
CC
Kenlan
Peter
P
Altintas
Mehmet M
MM
Wei
Changli
C
Faul
Christian
C
Herbert
Stephanie
S
Villegas
Ivan
I
Avila-Casado
Carmen
C
McGee
Mary
M
Sugimoto
Hikaru
H
Brown
Dennis
D
Kalluri
Raghu
R
Mundel
Peter
P
Smith
Paula L
PL
Clapham
David E
DE
Pollak
Martin R
MR
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
D015220:Calcium Channels; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human