Modulation of polycystic kidney disease severity by phosphodiesterase 1 and 3 subfamilies

Hong Ye, Xiaofang Wang, Caroline R. Sussman, Katharina Hopp, Maria Irazabal Mira, Jason L. Bakeberg, Wells B. LaRiviere, Vincent C. Manganiello, Charles V. Vorhees, Haiqing Zhao, Peter C Harris, Jan Van Deursen, Christopher J. Ward, Vicente Torres

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12 Scopus citations

Abstract

Aberrant intracellular calciumlevels 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 Pkd22/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 Pkd22/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 Pkd22/WS25;Pde1a2/2, Pkd22/WS25;Pde1c2/2, and Pkd22/WS25;Pde3a2/2 kidneys. The cystogenic effect of desmopressin administration was markedly enhanced in Pkd22/WS25;Pde3a2/2 mice, despite PDE3 accounting for only a small fraction of renal cAMP PDE activity. These observations show that calcium- and calmodulindependent 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.

Original languageEnglish (US)
Pages (from-to)1312-1320
Number of pages9
JournalJournal of the American Society of Nephrology
Volume27
Issue number5
DOIs
StatePublished - May 1 2016

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ASJC Scopus subject areas

  • Nephrology

Cite this

Ye, H., Wang, X., Sussman, C. R., Hopp, K., Irazabal Mira, M., Bakeberg, J. L., LaRiviere, W. B., Manganiello, V. C., Vorhees, C. V., Zhao, H., Harris, P. C., Van Deursen, J., Ward, C. J., & Torres, V. (2016). Modulation of polycystic kidney disease severity by phosphodiesterase 1 and 3 subfamilies. Journal of the American Society of Nephrology, 27(5), 1312-1320. https://doi.org/10.1681/ASN.2015010057