Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are important causes of end-stage renal failure without an effective therapy. Recent studies in our laboratory have shown upregulation of cAMP signaling that has been successfully targeted for treatment in animal models orthologous to human ADPKD and ARPKD. These studies have led to currently active clinical trials of arginine vasopressin (AVP) V2 receptor antagonists and long-acting somatostatin analogs. However, an animal model of the most common and severe form of ADPKD (PKD1) has not been tested, because until recently a model appropriate for preclinical trials was not available. Therefore Aim 1 in this application is to determine whether AVP V2R activation promotes the development of PKD in an animal model of ADPKD type 1, whether inhibition of V2R activation by pharmacologic or genetic means inhibits its development, and whether V2R antagonists and somatostatin analogs have a synergistic protective effect. The mechanisms responsible for the accumulation of cAMP in cystic tissues and for its effect on cystogenesis are not well understood. Preliminary studies in our laboratory have shown that phosphodiesterase 1 (PDE1), PDE3 and PDE4 activities and/or protein levels are reduced in cystic compared to wild-type kidneys and that cGMP (in addition to cAMP) levels are increased, pointing to a functional downregulation of PDE1, the only Ca2+ dependent PDE active against cGMP and cAMP. We propose that dysregulation of intracellular Ca2+ homeostasis in PKD activates positive feedback loops that result in sustained accumulation of cAMP (and cGMP) and activation of PKA and downstream signaling pathways responsible for increased rates of cell proliferation and apoptosis, fluid secretion and progression of the cystic disease. Differences in cyclic nucleotide metabolism and PDE profile in cystic tissues or freshly isolated tubules compared to cultured cells render in vitro systems inadequate to inform on cyclic nucleotide metabolism in vivo. Therefore we propose to a genetic strategy to study the role of specific PDE isoforms and downstream cAMP effectors in vivo (specific aims 2 and 3). This strategy is preferable to using currently available pharmacologic tools lack specificity.
Aim 2 will determine whether genetic inactivation of specific PDE1, PDE3 or PDE 4 isoforms enhances the development of PKD, and if so whether transgenic expression of the particular isoform has a protective effect.
Aim 3 will determine whether genetic inactivation of PKA regulatory subunits Ia or II? aggravates the development of PKD, and if so whether transgenic expression is protective. All mouse knockout lines necessary for these studies exist in our laboratory or are available from collaborators. Conditional kidney specific transgenes will be generated to confirm positive results only. These studies will advance the understanding of the pathogenesis of PKD, may identify disease modifiers underlying its marked phenotypic variability, and possibly lead to novel potential therapies (e.g. recently described PDE activators).

Public Health Relevance

Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are important causes of kidney failure for which there is no proven effective treatment. Treatments directed towards hormonal receptors that regulate the levels of cyclic AMP in tubular epithelial cells have been effective in animal models of ARPKD and of the less common of the two forms of ADPKD (PKD2). The proposed studies will determine whether they are also effective in a recently developed model of the most common and severe form of ADPKD (PKD1), will explore the possible synergism of treatments independently targeting cyclic AMP, and will utilize genetic tools to identify factors that may affect the accumulation of cAMP in cystic tissues and its effects on cyst growth and may contribute to the large inter- and intra-familial variability of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044863-18
Application #
8311036
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rasooly, Rebekah S
Project Start
1995-09-30
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$323,955
Indirect Cost
$118,530
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Chebib, Fouad T; Torres, Vicente E (2016) Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016. Am J Kidney Dis 67:792-810
Kline, Timothy L; Irazabal, Maria V; Ebrahimi, Behzad et al. (2016) Utilizing magnetization transfer imaging to investigate tissue remodeling in a murine model of autosomal dominant polycystic kidney disease. Magn Reson Med 75:1466-73
Ye, Hong; Wang, Xiaofang; Sussman, Caroline R et al. (2016) Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies. J Am Soc Nephrol 27:1312-20
Jung, Yeonsoon; Irazabal, María V; Chebib, Fouad T et al. (2016) Volume regression of native polycystic kidneys after renal transplantation. Nephrol Dial Transplant 31:73-9
Chebib, Fouad T; Sussman, Caroline R; Wang, Xiaofang et al. (2015) Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat Rev Nephrol 11:451-64
Torres, Vicente E (2015) Vasopressin receptor antagonists, heart failure, and polycystic kidney disease. Annu Rev Med 66:195-210
Hopp, Katharina; Wang, Xiaofang; Ye, Hong et al. (2015) Effects of hydration in rats and mice with polycystic kidney disease. Am J Physiol Renal Physiol 308:F261-6
Irazabal, Maria V; Mishra, Prasanna K; Torres, Vicente E et al. (2015) Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring. J Vis Exp :e52757
Muto, Satoru; Kawano, Haruna; Higashihara, Eiji et al. (2015) The effect of tolvaptan on autosomal dominant polycystic kidney disease patients: a subgroup analysis of the Japanese patient subset from TEMPO 3:4 trial. Clin Exp Nephrol 19:867-77
Hopp, Katharina; Hommerding, Cynthia J; Wang, Xiaofang et al. (2015) Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol 26:39-47

Showing the most recent 10 out of 76 publications