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).
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.
|Yu, Alan S L; Shen, Chengli; Landsittel, Douglas P et al. (2018) Baseline total kidney volume and the rate of kidney growth are associated with chronic kidney disease progression in Autosomal Dominant Polycystic Kidney Disease. Kidney Int 93:691-699|
|Nowak, Kristen L; You, Zhiying; Gitomer, Berenice et al. (2018) Overweight and Obesity Are Predictors of Progression in Early Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 29:571-578|
|Brosnahan, Godela M; Abebe, Kaleab Z; Moore, Charity G et al. (2018) Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials. Am J Kidney Dis 71:666-676|
|Besse, Whitney; Choi, Jungmin; Ahram, Dina et al. (2018) A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family. Hum Mutat 39:378-382|
|Cornec-Le Gall, Emilie; Torres, Vicente E; Harris, Peter C (2018) Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases. J Am Soc Nephrol 29:13-23|
|Torres, Vicente E; Chapman, Arlene B; Devuyst, Olivier et al. (2018) Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial. Nephrol Dial Transplant 33:477-489|
|Kline, Timothy L; Edwards, Marie E; Garg, Ishan et al. (2018) Quantitative MRI of kidneys in renal disease. Abdom Radiol (NY) 43:629-638|
|Wang, Xiaofang; Yamada, Satsuki; LaRiviere, Wells B et al. (2017) Generation and phenotypic characterization of Pde1a mutant mice. PLoS One 12:e0181087|
|Grantham, Jared J; Chapman, Arlene B; Blais, Jaime et al. (2017) Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease. Nephrol Dial Transplant 32:969-975|
|Devuyst, Olivier; Chapman, Arlene B; Gansevoort, Ron T et al. (2017) Urine Osmolality, Response to Tolvaptan, and Outcome in Autosomal Dominant Polycystic Kidney Disease: Results from the TEMPO 3:4 Trial. J Am Soc Nephrol 28:1592-1602|
Showing the most recent 10 out of 105 publications