Deficiency of polycystin‐2 reduces Ca2+channel activity and cell proliferation in ADPKD lymphoblastoid cells
Copyright policy )Deficiency of polycystin‐2 reduces Ca2+channel activity and cell proliferation in ADPKD lymphoblastoid cells
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.
- University of Ferrara Italy
- Leiden University Medical Center Netherlands
- Alma Mater Studiorum University of Bologna Italy
- New School United States
Mutation, Missense, Endoplasmic Reticulum, Kidney, PKD2 and PKD1 gene expression; real-time RT-PCR; PAF-induced calcium release; PKD mutations; aminoglycoside antibiotics, Humans, Point Mutation, Calcium Signaling, RNA, Messenger, Platelet Activating Factor, PKD2 and PKD1 gene expression ● real-time RT-PCR ● PAF-induced calcium release ● PKD mutations ● aminoglycoside antibiotics., Cell Line, Transformed, B-Lymphocytes, Ion Transport, PKD2 and PKD1 gene expression ● real-time RT-PCR ● PAF-induced calcium release ● PKD mutations ● aminoglycoside antibiotics, Membrane Proteins, Proteins, Polycystic Kidney, Autosomal Dominant, Amino Acid Substitution, Codon, Nonsense, Organ Specificity, Calcium, Gentamicins, Cell Division
Mutation, Missense, Endoplasmic Reticulum, Kidney, PKD2 and PKD1 gene expression; real-time RT-PCR; PAF-induced calcium release; PKD mutations; aminoglycoside antibiotics, Humans, Point Mutation, Calcium Signaling, RNA, Messenger, Platelet Activating Factor, PKD2 and PKD1 gene expression ● real-time RT-PCR ● PAF-induced calcium release ● PKD mutations ● aminoglycoside antibiotics., Cell Line, Transformed, B-Lymphocytes, Ion Transport, PKD2 and PKD1 gene expression ● real-time RT-PCR ● PAF-induced calcium release ● PKD mutations ● aminoglycoside antibiotics, Membrane Proteins, Proteins, Polycystic Kidney, Autosomal Dominant, Amino Acid Substitution, Codon, Nonsense, Organ Specificity, Calcium, Gentamicins, Cell Division
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