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(Circulation Research. 2009;104:860.)
© 2009 American Heart Association, Inc.

Cellular Biology

Ciliary Polycystin-2 Is a Mechanosensitive Calcium Channel Involved in Nitric Oxide Signaling Cascades

Wissam A. AbouAlaiwi, Maki Takahashi, Blair R. Mell, Thomas J. Jones, Shobha Ratnam, Robert J. Kolb, Surya M. Nauli

From the Department of Pharmacology (W.A.A., M.T., B.R.M., T.J.J., S.M.N.), College of Pharmacy; and Department of Medicine (S.R., S.M.N.), College of Medicine, University of Toledo, Ohio; and Department of Pediatrics (R.J.K.), Medical University of South Carolina, Charleston. Present address for T.J.J.: Pharmaceutical Sciences, Northeastern Universities Colleges of Medicine and Pharmacy, Rootstown, Ohio.

Correspondence to Surya M. Nauli, PhD, Departments of Pharmacology and Medicine, MS 607, Wolfe Hall building, Room 2243, University of Toledo, 2801 W Bancroft St, Toledo, OH 43606. E-mail Surya.Nauli{at}UToledo.edu

Cardiovascular complications such as hypertension are a continuous concern in patients with autosomal dominant polycystic kidney disease (ADPKD). The PKD2 encoding for polycystin-2 is mutated in 15% of ADPKD patients. Here, we show that polycystin-2 is localized to the cilia of mouse and human vascular endothelial cells. We demonstrate that the normal expression level and localization of polycystin-2 to cilia is required for the endothelial cilia to sense fluid shear stress through a complex biochemical cascade, involving calcium, calmodulin, Akt/PKB, and protein kinase C. In response to fluid shear stress, mouse endothelial cells with knockdown or knockout of Pkd2 lose the ability to generate nitric oxide (NO). Consistent with mouse data, endothelial cells generated from ADPKD patients do not show polycystin-2 in the cilia and are unable to sense fluid flow. In the isolated artery, we further show that ciliary polycystin-2 responds specifically to shear stress and not to mechanical stretch, a pressurized biomechanical force that involves purinergic receptor activation. We propose a new role for polycystin-2 in transmitting extracellular shear stress to intracellular NO biosynthesis. Thus, aberrant expression or localization of polycystin-2 to cilia could promote high blood pressure because of inability to synthesize NO in response to an increase in shear stress (blood flow).

Key Words: biophysical force • endothelia • mechanotransduction • primary cilium • shear stress