Polycystic kidney disease (PKD) is a "ciliopathic" disease since the loss of cilia or mutations in proteins involved in the function of cilia lead to renal cystic development. During embryonic development, deletion of cilia or mutations in cystoproteins such as polycystin 1 and 2 lead to PKD. However, in the adult animal, using conditional floxed alleles, to knockout cilia or delete cystoproteins, development of significant cystic disease only occurs after a number of months. The reason for this delay is not clear but it has provided a model to study factors or conditions that modify the initiation and progression of cystogenesis. This has led to the concept of a "third hit" in which an environmental influences, physiological adaptive responses, or associated pathophysiological conditions initiates and accelerates cystogenesis. Previous work has shown that acute kidney injury can accelerate cystogenesis. Recently we have shown that reduced renal mass also accelerates the formation of cysts. Finally, it has been reported in humans that kidney size, which is an index of cystic burden, is doubled in diabetic versus non-diabetic autosomal dominant PKD patients. Thus, hypertrophic signaling and hyperglycemia may be two extremely important regulators of disease progression in PKD. Hypothesis: That the presence of reduced renal mass or elevated blood glucose levels result in the initiation and acceleration of cystogenesis in mouse models of PKD. In addition, lack of cilia or mutations in cystoproteins may affect the renal adaptive response to hypertrophy and hyperglycemia Specific objectives: (1) investigate reduced renal mass (nephrectomy), hyperglycemia (diabetes), or both as third hits that accelerate cystogenesis;(2) determine if cilia or cystoproteins modulates renal hypertrophy and affects disease progression thereby leading to accelerated diabetic nephropathy;and (3) unravel the complex signaling processes that result in cystogenesis. Determine how these pathways are altered in the presence of hyperglycemia and hypertrophic signaling. Relevance: In ADPKD, cyst progression is highly variable and understanding what triggers initiation and what regulates cyst progression has become a major focus in PKD research. The studies outlined in this application will provide new and important information on what regulates the onset and progression of cystogenesis. Procedures to be used: Adult mice with and without PKD will be studied in presence or absence of nephrectomy to reduce renal mass or after induction of diabetes with streptozotocin or in the presence of both conditions. Light and electron microscopy will be used to study cystic development and assess pathological changes in kidney and other organs and in cell culture models. Physiological studies will be performed to assess GFR, blood pressure, and proteinuria, Western blot, immunofluorescence, genomic analysis will be used to evaluate the complex signaling pathways that are activated in these models. Significance of potential new findings: Only recently has hypertrophic signaling and hyperglycemia been identified as playing critical roles in the initiation and rate of cyst progression in PKD. In addition the role of cilia in controlling structural and functional hypertrophy and in the renal response to diabetes has not been studied. This work may lead to new approaches to arrest or slow the progression of cystic disease. Potential impact on Veterans health care: Autosomal Dominant Polycystic kidney disease affects both males and females of all ethnicities with symptoms beginning between 30 and 40 years of age. It is a devastating disease that usually results in renal failure with treatment options limited to dialysi and transplantation. There are also cardiovascular effects including hypertension and stroke. For reasons that are not clear, the incidence of PKD reported in the VA population is nearly double of that found in the general non- VA population. Thus there is a compelling reason to focus on this disease and its effective treatment or cure, which would greatly benefit the VA patient population.

Public Health Relevance

Polycystic Kidney Disease (PKD) is a devastating genetic condition in which cysts form in the kidney, ultimately leading to renal failure. At the present time there is no known effective treatment for this disease. Autosomal dominant PKD (ADPKD) occurs in adults and is caused by mutations in two proteins polycystin 1 and 2. The incidence of ADPKD for the VA patient population is at least double compared to the general population of the United States. The progression of PKD is highly variable and this may be due to associated factors that affect disease progression. The work that is proposed in this application is focused on understanding the role of reduced kidney mass (hypertrophic signaling) and diabetes (hyperglycemia) on initiation and progression of cystogenesis. The ultimate goal of this research is to identify molecular targets for drug design in order to slow or prevent cystic development. If possible this would be of enormous benefit to the VA patients who have ADPKD.

Agency
National Institute of Health (NIH)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002007-02
Application #
8668721
Study Section
Nephrology (NEPH)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ralph H Johnson VA Medical Center
Department
Type
DUNS #
City
Charleston
State
SC
Country
United States
Zip Code
29401