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

被引:22
作者
Aguiari, Gianluca [1 ]
Varani, Katia [2 ]
Bogo, Marco [1 ]
Mangolini, Alessandra [1 ]
Vincenzi, Fabrizio [2 ]
Durante, Chiara [1 ]
Gessi, Stefania [2 ]
Sacchetto, Valeria [2 ]
Catizone, Luigi [4 ]
Harris, Peter [5 ]
Rizzuto, Rosario [3 ]
Borea, Pier Andrea [2 ]
del Senno, Laura [1 ]
机构
[1] Univ Ferrara, Dept Biochem & Mol Biol, Mol Biol Sect, I-44100 Ferrara, Italy
[2] Univ Ferrara, Dept Clin & Expt Med, Pharmacol Unit, I-44100 Ferrara, Italy
[3] Univ Ferrara, Dept Expt & Diagnost Med, Sect Gen Pathol, I-44100 Ferrara, Italy
[4] St Anna Hosp, Div Nephrol, Ferrara, Italy
[5] Mayo Clin, Coll Med, Div Nephrol & Hypertens, Rochester, MN 55905 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2009年 / 1792卷 / 06期
关键词
ADPKD; Polycystin-1; Adenosine receptor; cAMP-dependent signalling; NFkB activation; Renal cell; C-TERMINAL FRAGMENT; NF-KAPPA-B; EPITHELIAL-CELLS; CYCLIC-AMP; G-PROTEINS; ACTIVATION; PATHWAY; KINASE; ERK; PHOSPHORYLATION;
D O I
10.1016/j.bbadis.2009.03.001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 A(3) adenosine receptor via an NFkB-dependent mechanism. Interestingly, A(3) 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 p21(waf) 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 A(3)AR expression in cystic cells. (C) 2009 Elsevier B.V. All rights reserved.
引用
收藏
页码:531 / 540
页数:10
相关论文
共 47 条
[1]   Novel role for polycystin-1 in modulating cell proliferation through calcium oscillations in kidney cells [J].
Aguiari, G. ;
Trimi, V. ;
Bogo, M. ;
Mangolini, A. ;
Szabadkai, G. ;
Pinton, P. ;
Witzgall, R. ;
Harris, P. C. ;
Borea, P. A. ;
Rizzuto, R. ;
del Senno, L. .
CELL PROLIFERATION, 2008, 41 (03) :554-573
[2]   Deficiency of polycystin-2 reduces Ca2+ channel activity and cell proliferation in ADPKD lymphoblastoid cells [J].
Aguiari, G ;
Banzi, M ;
Gessi, S ;
Cai, YQ ;
Zeggio, E ;
Manzati, E ;
Piva, R ;
Lambertini, E ;
Ferrari, L ;
Peters, DJ ;
Lanza, F ;
Harris, PC ;
Borea, PA ;
Somlo, S ;
del Senno, L .
FASEB JOURNAL, 2004, 18 (03) :884-+
[3]   Expression of polycystin-1 C-terminal fragment enhances the ATP-induced Ca2+ release in human kidney cells [J].
Aguiari, G ;
Campanella, M ;
Manzati, E ;
Pinton, P ;
Banzi, M ;
Moretti, S ;
Piva, R ;
Rizzuto, R ;
del Senno, L .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2003, 301 (03) :657-664
[4]   PKD1 induces p21waf1 and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2 [J].
Bhunia, AK ;
Piontek, K ;
Boletta, A ;
Liu, LJ ;
Qian, F ;
Xu, PN ;
Germino, FJ ;
Germino, GG .
CELL, 2002, 109 (02) :157-168
[5]   Activation of the A3 adenosine receptor affects cell cycle progression and cell growth [J].
Brambilla, R ;
Cattabeni, F ;
Ceruti, S ;
Barbieri, D ;
Franceschi, C ;
Kim, YC ;
Jacobson, KA ;
Klotz, KN ;
Lohse, MJ ;
Abbracchio, MP .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2000, 361 (03) :225-234
[6]   Strategies to inhibit cyst formation in ADPKD [J].
Calvet, James P. .
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2008, 3 (04) :1205-1211
[7]   ERK implication in cell cycle regulation [J].
Chambard, Jean-Claude ;
Lefloch, Renaud ;
Pouyssegur, Jacques ;
Lenormand, Philippe .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2007, 1773 (08) :1299-1310
[8]   Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2 [J].
Delmas, P ;
Nomura, H ;
Li, XG ;
Lakkis, M ;
Luo, Y ;
Segal, Y ;
Fernández-Fernández, JM ;
Harris, P ;
Frischauf, AM ;
Brown, DA ;
Zhou, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (13) :11276-11283
[9]   Mesangial cell apoptosis induced by stimulation of the adenosine A3 receptor:: Signaling and apoptotic events [J].
Duann, P ;
Ho, TY ;
Desai, BD ;
Kapoian, T ;
Cowen, DS ;
Lianos, EA .
JOURNAL OF INVESTIGATIVE MEDICINE, 2005, 53 (01) :37-43
[10]   An agonist to the A3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3β and NF-κB [J].
Fishman, P ;
Bar-Yehuda, S ;
Ohana, G ;
Barer, F ;
Ochaion, A ;
Erlanger, A ;
Madi, L .
ONCOGENE, 2004, 23 (14) :2465-2471