Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening genetic disease affecting 600,000 Americans and 12.5 million people worldwide. ADPKD is characterized by the development and growth of multiple renal cysts that eventually replace the normal renal parenchyma resulting in ultimate loss of renal function. Moreover, early onset of hypertension in ADPKD patients and increased incidence of left ventricular hypertrophy are associated with heightened mortality risk. Despite discovery of the causative genes associated with ADPKD more than a decade ago, the factors that affect the growth of renal cysts and hence the progression of renal disease remain largely unknown. There are similarities between cyst growth in ADPKD and growth of a benign tumor;namely increased proliferation of the cystic renal epithelial cells and angiogenesis occurring on the surface of renal cysts. In this proposal we seek to characterize the angiogenic changes associated with cyst growth, renal injury and cardiac damage across the spectrum of ADPKD severity. We propose a novel approach to the study of cystogenesis with focus on human studies. Accordingly, based on our preliminary data we hypothesize that that aberrant expression of angiogenic growth factors plays a role in all stages of the pathogenesis of ADPKD. Specifically, we propose that local up-regulated expression of pro-angiogenic growth factors stimulates renal cyst growth as manifest by changes in renal structure. In addition, elevated expression levels of angiogenic growth factors are associated with cardiac structural damage assessed by increase in left ventricular mass. Thus, the specific aims of this proposal are to characterize the changes in both circulating and urinary angiogenic growth factor levels at different stages of disease progression and their relationship with renal structure and function and cardiac structure. In a more experimental aim exfoliated renal cells recovered from urine of patients with different stages of renal disease severity based on kidney volume will be used to examine expression of angiogenic mediators at the mRNA and protein level. The results of these studies will impact future research directions in ADPKD. In particular, positive results of the proposed study should inform about the planning of a large, definitive, interventional study in patients with ADPKD.

Public Health Relevance

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening genetic disease affecting 600,000 Americans and 12.5 million people worldwide. In order to develop effective therapies for ADPKD an understanding of the mechanisms that influence cyst growth and promote renal injury is necessary. Our discovery of new factors that influence the growth of kidney cysts will improve understanding of disease pathogenesis and stimulate development of new therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK090005-02
Application #
8332110
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Flessner, Michael Francis
Project Start
2011-09-20
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$229,500
Indirect Cost
$79,500
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045