TRPC6 enhances angiotensin II-induced albuminuria.
Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6-deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell-membrane currents in primary cultures of podocytes from both wild-type and TRPC6-deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca(2+), suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease.
Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Jason
J
Eckel
Peter J
PJ
Lavin
Elizabeth A
EA
Finch
Nirvan
N
Mukerji
Jarrett
J
Burch
Rasheed
R
Gbadegesin
Guanghong
G
Wu
Brandy
B
Bowling
Alison
A
Byrd
Gentzon
G
Hall
Matthew
M
Sparks
Zhu Shan
ZS
Zhang
Alison
A
Homstad
Laura
L
Barisoni
Lutz
L
Birbaumer
Paul
P
Rosenberg
Michelle P
MP
Winn
D000419:Albuminuria / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D000804:Angiotensin II / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D006973:Hypertension / Q000503:physiopathology; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D000804:Angiotensin II; D002118:Calcium
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