Induction of TRPC6 channel in acquired forms of proteinuric kidney disease.
Injury to podocytes and their slit diaphragms typically leads to marked proteinuria. Mutations in the TRPC6 gene that codes for a slit diaphragm-associated, cation-permeable ion channel have been shown recently to co-segregate with hereditary forms of progressive kidney failure. Herein is shown that induced expression of wild-type TRPC6 is a common feature of human proteinuric kidney diseases, with highest induction observed in membranous nephropathy. Cultured podocytes that are exposed to complement upregulate TRPC6 protein. Stimulation of receptor-operated channels in puromycin aminonucleoside-treated podocytes leads to increased calcium influx in a time- and dosage-dependent manner. Mechanistically, it is shown that TRPC6 is functionally connected to the podocyte actin cytoskeleton, which is rearranged upon overexpression of TRPC6. Transient in vivo gene delivery of TRPC6 into mice leads to expression of TRPC6 protein at the slit diaphragm and causes proteinuria. These studies suggest the involvement of TRPC6 in the pathology of nongenetic forms of proteinuric disease.
Möller
Clemens C
CC
Department of Medicine, Nephrology Division, Massachusetts General Hospital and Harvard Medical School, MGH-East, 149 13th Street, Boston, MA 02129, USA.
Wei
Changli
C
Altintas
Mehmet M
MM
Li
Jing
J
Greka
Anna
A
Ohse
Takamoto
T
Pippin
Jeffrey W
JW
Rastaldi
Maria P
MP
Wawersik
Stefan
S
Schiavi
Susan
S
Henger
Anna
A
Kretzler
Matthias
M
Shankland
Stuart J
SJ
Reiser
Jochen
J
D000818:Animals; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050052:TRPC Cation Channels / Q000096:biosynthesis* / Q000235:genetics; D000074287:TRPC6 Cation Channel; D014162:Transfection
D012333:RNA, Messenger; D011994:Recombinant Proteins; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human