Polycystic kidney disease (PKD) is a systemic nephropathy characterized by progressive bilateral renal cyst formation that results in a gradual decline in renal function. Although it is most commonly categorized as a kidney disease, the majority of patients with PKD die due to cardiovascular complications such as hypertension, aneurysm, hemorrhage, etc. Nonetheless, very little attention has been focused on the basic science aspects of these complications. We believe that PKD is associated with both genetic and functional defects in mechanosensory cilia, causing aberrant calcium signaling that lead to cardiovascular complications. Here, we hypothesize that primary cilia play an important role in fluid-shear sensing in endothelial cells. Using endothelial cells from Pkd mouse models (such as Tg737, Pkd1, and Pkd2), we will study whether Pkd endothelial cells have biomechanical dysfunction in fluid-shear sensing similar to those previously demonstrated in Pkd epithelial cells. We will further study whether cilia, acting as mechanical-sensory organelles, have unique biophysical abilities to sense fluid-shear stress. Given that all cells are capable of sensing extracellular signals, we intend to ask how specific is the mechanical sensing by cilia. We will use a set of different stimuli to examine the specificity of cilia in fluid-shear sensing. We will compare cellular responses induced by fluid-shear stress, plasma membrane distortion, and pharmacological ligands. We will use both biophysical (calcium) and biochemical (nitric oxide) properties of endothelial cells to study their involvement in mechanofluid sensing. Thus, the present proposal is positioned to provide new insights into mechanisms of cardiovascular diseases, such as hypertension, in both PKD and non-PKD patients. The proposed study will also advance scientific understanding of cilia biology in fluid sensing related to cardiovascular physiology and pathophysiology.

Public Health Relevance

Although PKD is often described as one of the most common human genetic diseases;only 4% of the cases of new end-stage renal disease (ESRD) have been in the cystic disease category. On the other hand, hypertension is the second most common cause of ESRD and is one of the leading causes of cardiovascular death. Because the pathogenesis of hypertension in PKD is still unknown, the present proposal is designed to understand the molecular pathology of hypertension and to offer information enabling more precise and specific pharmacological interventions with the potential to effectively treat or reduce high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080640-05
Application #
8320397
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Rasooly, Rebekah S
Project Start
2008-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$299,910
Indirect Cost
$91,639
Name
University of Toledo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
051623734
City
Toledo
State
OH
Country
United States
Zip Code
43606
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