Deficiency of polycystic kidney disease-1 gene (PKD1) expression increases A3 adenosine receptors in human renal cells: Implications for cAMP-dependent signalling and proliferation of PKD1-mutated cystic cells

Gianluca Aguiari, Katia Varani, Marco Bogo, Alessandra Mangolini, Fabrizio Vincenzi, Chiara Durante, Stefania Gessi, Valeria Sacchetto, Luigi Catizone, Peter Harris, Rosario Rizzuto, Pier Andrea Borea, Laura del Senno

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Cyst growth and expansion in autosomal dominant polycystic kidney disease (ADPKD) has been attributed to numerous factors, including ATP, cAMP and adenosine signalling. Although the role of ATP and cAMP has been widely investigated in PKD1-deficient cells, no information is currently available on adenosine-mediated signalling. Here we investigate for the first time the impact of abnormalities of polycystin-1 (PC1) on the expression and functional activity of adenosine receptors, members of the G-protein-coupled receptor superfamily. Pharmacological, molecular and biochemical findings show that a siRNA-dependent PC1-depletion in HEK293 cells and a PKD1-nonsense mutation in cyst-derived cell lines result in increased expression of the A3 adenosine receptor via an NFkB-dependent mechanism. Interestingly, A3 adenosine receptor levels result higher in ADPKD than in normal renal tissues. Furthermore, the stimulation of this receptor subtype with the selective agonist Cl-IB-MECA causes a reduction in both cytosolic cAMP and cell proliferation in both PC1-deficient HEK293 cells and cystic cells. This reduction is associated with increased expression of p21waf and reduced activation not only of ERK1/2, but also of S6 kinase, the main target of mTOR signalling. In the light of these findings, the ability of Cl-IB-MECA to reduce disease progression in ADPKD should be further investigated. Moreover, our results suggest that NFkB, which is markedly activated in PC1-deficient and cystic cells, plays an important role in modulating A3AR expression in cystic cells.

Original languageEnglish (US)
Pages (from-to)531-540
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1792
Issue number6
DOIs
StatePublished - Jun 1 2009

Keywords

  • ADPKD
  • Adenosine receptor
  • NFkB activation
  • Polycystin-1
  • Renal cell
  • cAMP-dependent signalling

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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