RESUMEN
Polycystin-2 (PC-2), a protein encoded by PKD2 and involved in autosomal dominant polycystic kidney disease (ADPKD), is a non-selective cationic channel recently implicated in the function of primary cilia. We recently constructed a new animal model in the form of a transgenic mouse with a BAC-containing human PKD2 inserted in its genome. Two transgenic mouse lines overexpressing human PKD2 showed mitotic instability. Fibroblasts from these transgenic mouse lines have abnormal chromosomal numbers. These lines also have supernumerary centrosomes. PC-2 overexpression is associated with mitotic instability and centrosome overduplication. PC-2 therefore seems to play a role in centrosome duplication, and this hypothesis is being evaluated in other models.
Asunto(s)
Centrosoma/metabolismo , Inestabilidad Cromosómica , Ratones Transgénicos , Mitosis/genética , Canales Catiónicos TRPP/genética , Aneuploidia , Animales , Células Cultivadas , Fibroblastos/citología , Fibroblastos/fisiología , Humanos , Masculino , Ratones , Ratones Noqueados , Riñón Poliquístico Autosómico Dominante/genética , Riñón Poliquístico Autosómico Dominante/metabolismo , Huso Acromático/metabolismo , Canales Catiónicos TRPP/metabolismo , TransgenesRESUMEN
Polycystin-2 (PC-2), a cation channel of the Trp family, is involved in autosomal dominant polycystic kidney disease (ADPKD) type 2 (ADPKD2). This protein has recently been localized to the primary cilium where its channel function seems to be involved in a mechanosensory phenomenon. However, its biological function is not totally understood, especially in tubule formation. In the present paper, we describe a mouse model for human PC-2 overexpression, obtained by inserting a human bacterial artificial chromosome (BAC) containing the PKD2 gene. Three lines were generated, expressing different levels of PKD2. One line, PKD2-Y, has been explored in more detail and we will present physiological and molecular exploration of these transgenic animals. Our data demonstrate that transgenic animals older than 12 months present tubulopathy with proteinuria and failure to concentrate urine. Moreover, the kidney cortex has been found disorganized. Finally, we observe that extracellular matrix protein expression is downregulated in these animals. In conclusion, overexpression of human PKD2 leads to anomalies in tubular function, probably due to abnormalities in tubule morphogenesis.
