title: Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies.
abstract: Aberrant intracellular calcium levels and increased cAMP signaling contribute to the development of polycystic kidney disease (PKD). cAMP can be hydrolyzed by various phosphodiesterases (PDEs). To examine the role of cAMP hydrolysis and the most relevant PDEs in the pathogenesis of PKD, we examined cyst development in Pde1- or Pde3-knockout mice on the Pkd2(-/WS25) background (WS25 is an unstable Pkd2 allele). These PDEs were selected because of their importance in cross-talk between calcium and cyclic nucleotide signaling (PDE1), control of cell proliferation and cystic fibrosis transmembrane conductance regulator (CFTR) -driven fluid secretion (PDE3), and response to vasopressin V2 receptor activation (both). In Pkd2(-/WS25) mice, knockout of Pde1a, Pde1c, or Pde3a but not of Pde1b or Pde3b aggravated the development of PKD and was associated with higher levels of protein kinase A-phosphorylated (Ser133) cAMP-responsive binding protein (P-CREB), activating transcription factor-1, and CREB-induced CRE modulator proteins in kidney nuclear preparations. Immunostaining also revealed higher expression of P-CREB in Pkd2(-/) (WS25);Pde1a(-/-), Pkd2(-) (/WS25);Pde1c(-/-), and Pkd2(-/) (WS25);Pde3a(-/-) kidneys. The cystogenic effect of desmopressin administration was markedly enhanced in Pkd2(-/WS25);Pde3a(-/-) mice, despite PDE3 accounting for only a small fraction of renal cAMP PDE activity. These observations show that calcium- and calmodulin-dependent PDEs (PDE1A and PDE1C) and PDE3A modulate the development of PKD, possibly through the regulation of compartmentalized cAMP pools that control cell proliferation and CFTR-driven fluid secretion. Treatments capable of increasing the expression or activity of these PDEs may, therefore, retard the development of PKD.
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Caroline R
authors.initials: CR
authors.lastname: Sussman
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hopp
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Irazabal
authors.affiliation: Division of Nephrology and Hypertension, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Jason L
authors.initials: JL
authors.lastname: Bakeberg
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Wells B
authors.initials: WB
authors.lastname: LaRiviere
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung and Blood Institute, US National Institutes of Health, Bethesda, Maryland;
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Manganiello
authors.affiliation: Department of Pediatrics, Division of Neurology, Cincinnati Children's Research Foundation and University of Cincinnati, Cincinnati, Ohio; and.
authors.forename: Charles V
authors.initials: CV
authors.lastname: Vorhees
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Division of Nephrology and Hypertension and.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Jan
authors.initials: J
authors.lastname: van Deursen
authors.affiliation: Division of Nephrology and Hypertension, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ward
authors.affiliation: Division of Nephrology and Hypertension and torres.vicente@mayo.edu.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
mesh_terms: D000818:Animals; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D007690:Polycystic Kidney Diseases / Q000201:enzymology* / Q000209:etiology; D012720:Severity of Illness Index
chemical_list: D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C527988:Pde1A protein, mouse; C517273:Pde1C protein, mouse; C517289:Pde3a protein, mouse
keywords: cAMP; cystic kidney; polycystic kidney disease