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Publisher: Nature Publishing Group
Languages: English
Types: Article
Subjects: Article

Classified by OpenAIRE into

mesheuropmc: urogenital system, urologic and male genital diseases, female genital diseases and pregnancy complications
Tubular cell proliferation occurs early and precedes cyst formation in autosomal dominant polycystic kidney disease (ADPKD). To identify key alterations in cell signalling which regulate cell proliferation in ADPKD, we examined the potential role of insulin-like growth factor-1 (IGF-1) mediated signalling pathways. Conditionally immortalised tubular epithelial cells were generated from ADPKD patients with characterised germline PKD1 mutations and normal individuals. Germline and somatic PKD1 (but not PKD2) mutations were identified in PKD1 cystic cells by DHPLC. All lines showed a reduction or absence of polycystin-1 but normal polycystin-2 expression. Polycystin-1 deficiency was associated with increased sensitivity to IGF-1 as well as a permissive effect of cAMP on cell growth. The increase in cell proliferation to both agents was dependent on PI3 kinase and ERK activity. Inhibition of Ras or Raf activity also abolished stimulated cell proliferation. Ras activation assays revealed significantly higher IGF-1 stimulated levels of GTP-Ras in cystic cells compared to control cells but cAMP alone had no effect on GTP-Ras levels. These results suggest that haploinsufficiency of PC1 may lower the threshold for activation of a Ras-Raf mediated signalling cascade leading to growth-factor induced hyperproliferation. Inhibition of Ras or Raf activation could be a useful therapeutic approach to reducing tubular cell proliferation in ADPKD.
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