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Ciliotherapy： a novel intervention in polycystic kidney disease

Journal of Geriatric Cardiology 2014年第1期11卷 63-73页

作者： Sarmed H. Kathem Ashraf M. Mohieldin Shakila Abdul-Majeed Sajida H. Ismail Qaiss H. Altaei Ibrahim K. Alshimmari Mohanned M. Alsaidi Hussein Khammas Andromeda M. Nauli bina joe Surya M. Nauli Centerfor Hypertension and Personalized Medicine University of Toledo Health Science Building Room 312 3000 Arlington Ave. Toledo OH 43614 USA Department of Pharmacology University of Toledo Health Education Building Room 274 3000 Arlington Ave. Toledo OH 43614 USA College of Pharmacy University of Baghdad Bab-Almoadhum 14026 Baghdad Iraq Kidney Disease and Transplant Center Medical City Complex Bab-Almoadhum 14026 Baghdad Iraq Alkadhumia Academic Hospital Bab-Almoadhum 14026 Baghdad Iraq pharmaceutical & Biomedical Sciences California Northstate University 10811 International Drive Rancho Cordova CA 95670 USA

Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertension. We previously showed that cilia length regulates cilia function, and cilia function is required for nitric oxide （NO） biosynthesis in endothelial cells. Because patients with PKD show abnormal sensory cilia function, the aim of our current study was to search for a targeted therapy focused on primary cilia, which we refer to as ＇cilio- therapy＇. Methods and Results In the present studies, our in vitro analyses refined fenoldopam as an equipotent and more specific dopa- minergic agonist to regulate cilia length and function. Our in vivo studies indicated that fenoldopam increased cilia length and serum NO thereby reducing blood pressure in a PKD mouse model. Our crossover, multicenter, double-blind and placebo-controlled clinical study further indicated that cilia-targeting therapy showed an overall reduction in mean arterial pressure in PKD patients. Conclusions Overall, our studies provide the first evidence of ciliotherapy as an innovative intervention in patients with abnormal primary cilia.

关键词： Primary cilium Blood pressure Mechanosensor Mechanotransduction Chemosensor Fluid-shear stress

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