Inhibition of the TRPC5 ion channel protects the kidney filter.
An intact kidney filter is vital to retention of essential proteins in the blood and removal of waste from the body. Damage to the filtration barrier results in albumin loss in the urine, a hallmark of cardiovascular disease and kidney failure. Here we found that the ion channel TRPC5 mediates filtration barrier injury. Using Trpc5-KO mice, a small-molecule inhibitor of TRPC5, Ca2+ imaging in isolated kidney glomeruli, and live imagining of podocyte actin dynamics, we determined that loss of TRPC5 or its inhibition abrogates podocyte cytoskeletal remodeling. Inhibition or loss of TRPC5 prevented activation of the small GTP-binding protein Rac1 and stabilized synaptopodin. Importantly, genetic deletion or pharmacologic inhibition of TRPC5 protected mice from albuminuria. These data reveal that the Ca2+-permeable channel TRPC5 is an important determinant of albuminuria and identify TRPC5 inhibition as a therapeutic strategy for the prevention or treatment of proteinuric kidney disease.
Thomas
T
Schaldecker
Sookyung
S
Kim
Constantine
C
Tarabanis
Dequan
D
Tian
Samy
S
Hakroush
Philip
P
Castonguay
Wooin
W
Ahn
Hanna
H
Wallentin
Hans
H
Heid
Corey R
CR
Hopkins
Craig W
CW
Lindsley
Antonio
A
Riccio
Lisa
L
Buvall
Astrid
A
Weins
Anna
A
Greka
D000419:Albuminuria / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D000595:Amino Acid Sequence; D000818:Animals; D020013:Calcium Signaling; D060730:Glomerular Filtration Barrier / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000648:ultrastructure; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000378:metabolism; D050199:Podocytes / Q000648:ultrastructure; D011479:Protamines / Q000633:toxicity; D051381:Rats; D050052:TRPC Cation Channels / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D008070:Lipopolysaccharides; D009479:Neuropeptides; D011479:Protamines; C484602:Rac1 protein, mouse; D050052:TRPC Cation Channels; C491780:TRPC5 protein, human; C112021:Trpc5 protein, mouse; C503500:Trpc5 protein, rat; D020830:rac1 GTP-Binding Protein