Journal
CELL
Volume 139, Issue 3, Pages 587-596Publisher
CELL PRESS
DOI: 10.1016/j.cell.2009.08.045
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Funding
- ANR 2005 cardiovasculaire-obesite-diabete
- ANR 2008 du gene a la physiopathologie
- Association for information and research on genetic kidney disease France
- Fondation del Duca
- Fondation de la recherche medicale
- Fondation de France
- EEC Marie-Curie [039328]
- Fondation de recherche sur l'hypertension arterielle
- Fondation de la recherche sur le cerveau
- Human Frontier Science [LT-00555]
- Societe Generale AM
- Universite de Nice Sophia Antipolis
- Centre National de la Recherche Scientifique
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Autosomal-dominant polycystic kidney disease, the most frequent monogenic cause of kidney failure, is induced by mutations in the PKD1 or PKD2 genes, encoding polycystins TRPP1 and TRPP2, respectively. Polycystins are proposed to form a flow-sensitive ion channel complex in the primary cilium of both epithelial and endothelial cells. However, how polycystins contribute to cellular mechanosensitivity remains obscure. Here, we show that TRPP2 inhibits stretch-activated ion channels (SACs). This specific effect is reversed by coexpression with TRPP1, indicating that the TRPP1/TRPP2 ratio regulates pressure sensing. Moreover, deletion of TRPP1 in smooth muscle cells reduces SAC activity and the arterial myogenic tone. Inversely, depletion of TRPP2 in TRPP1-deficient arteries rescues both SAC opening and the myogenic response. Finally, we show that TRPP2 interacts with filamin A and demonstrate that this actin crosslinking protein is critical for SAC regulation. This work uncovers a role for polycystins in regulating pressure sensing.
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