Polycystin-2 (PC2), encoded by the PKD2 gene, mutated in 10-15% of autosomal-dominant polycystic kidney disease (ADPKD) patients, is a Ca2+-permeable cation channel present in kidney epithelia and other tissues. As PC2 was found expressed in B-lymphoblastoid cells (LCLs) and Ca2+ signaling pathways are important regulators of B cell function activities, we investigated whether PC2 plays some role in B-LCLs. In LCLs, PC2 was found mainly in ER membranes but ~8 times less than in kidney HEK293 cells. The same reductions were found in PKD2 and PKD1 RNA; thus, PKD genes maintained, in LCLs, the same reciprocal proportion as they do in kidney cells. In LCLs obtained from subjects carrying PKD2 mutations (PKD2-LCLs) and showing reduced PC2 levels, intracellular Ca2+ concentrations evoked by platelet-activating factor (PAF), were significantly lower than in non-PKD-LCLs. This reduction was also found in PKD1-LCLs but without PC2 reductions. Likewise, cell proliferation, which is controlled by Ca2+, was reduced in PKD2- and PKD1-LCLs. Moreover, in LCLs with PKD2 nonsense mutations, aminoglycoside antibiotics reduced the PC2 defect by promoting readthrough of stop codons. Therefore, PC2 and PC1 are functionally expressed in LCLs, which provide a model, easily obtainable from ADPKD patients, to study PKD gene expression and function.

Deficiency of polycystin-2 reduces Ca2+ channel activity and cell proliferation in ADPKD lymphoblastoid cells

AGUIARI, Gianluca
Primo
;
GESSI, Stefania;MANZATI, ELISA;PIVA, Maria Roberta;LAMBERTINI, Elisabetta;LANZA F;BOREA, Pier Andrea;DEL SENNO, Laura
Ultimo
2004

Abstract

Polycystin-2 (PC2), encoded by the PKD2 gene, mutated in 10-15% of autosomal-dominant polycystic kidney disease (ADPKD) patients, is a Ca2+-permeable cation channel present in kidney epithelia and other tissues. As PC2 was found expressed in B-lymphoblastoid cells (LCLs) and Ca2+ signaling pathways are important regulators of B cell function activities, we investigated whether PC2 plays some role in B-LCLs. In LCLs, PC2 was found mainly in ER membranes but ~8 times less than in kidney HEK293 cells. The same reductions were found in PKD2 and PKD1 RNA; thus, PKD genes maintained, in LCLs, the same reciprocal proportion as they do in kidney cells. In LCLs obtained from subjects carrying PKD2 mutations (PKD2-LCLs) and showing reduced PC2 levels, intracellular Ca2+ concentrations evoked by platelet-activating factor (PAF), were significantly lower than in non-PKD-LCLs. This reduction was also found in PKD1-LCLs but without PC2 reductions. Likewise, cell proliferation, which is controlled by Ca2+, was reduced in PKD2- and PKD1-LCLs. Moreover, in LCLs with PKD2 nonsense mutations, aminoglycoside antibiotics reduced the PC2 defect by promoting readthrough of stop codons. Therefore, PC2 and PC1 are functionally expressed in LCLs, which provide a model, easily obtainable from ADPKD patients, to study PKD gene expression and function.
Aguiari, Gianluca; Banzi, M; Gessi, Stefania; Cai, Y; Zeggio, E; Manzati, Elisa; Piva, Maria Roberta; Lambertini, Elisabetta; Ferrari, L; Peters, Dj; Lanza, F; Harris, Pc; Borea, Pier Andrea; Somlo, S; DEL SENNO, Laura
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1207659
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