Abstract P369: The Role Of Primary Cilia In The Pathogenesis And Therapy Of Hypertension In Polycystic Kidney Disease.

Abstract

Primary cilia are sensory organelles, extending from the surface of vascular endothelialcells. Primary cilia dysfunctions have been linked to numerous genetic disorders,including polycystic kidney disease (PKD). Although PKD is characterized by fluid-filledcystic kidneys, cardiovascular complications such as hypertension (HTN) are the leadingcause of death in PKD patients. We demonstrated that primary cilia sense and transmitexternal mechanical stimuli such as fluid shear stress into internal biochemical reactionssuch as the release of nitric oxide (NO). This idea has only been investigated in ECs invitro . However, the importance of the vascular primary cilia in the long-term regulationof BP has not been investigated. NO-induced vasodilation is also produced in response tostimulation of eNOS by muscarinic acetylcholine receptor 3 (AChM3R) activation byacetylcholine (ACh). Using immunofluorescence staining, we generated new andsurprising data showing that AChM3R, and its signaling components, PIP2 are localizedto primary cilia and can modulate cilia function. We hypothesize that primary ciliacontribute to BP regulation in PKD through AChM3R. We showed that both, selective(cevimeline) and non-selective (ACh, CCh) activation of AChM3R led to an increase incilia length and cilia sensory function in terms of p-eNOS expression. We also generatedendothelial-specific ( Tie2Cre and VECre ) AChM3R KO mouse lines, in which AChM3R was deleted from the vascular endothelia. These mice developed high BP, as measured bytail cuff and telemetry blood pressure monitoring devices, associated with attenuated NOproduction and impaired vascular relaxation in response to ACh stimulation. Thesestudies demonstrated the physiological significance of primary cilia-derived NO in thelong-term control of vascular hemodynamics.