ACIDIC FGF REGULATION OF HYPERPROLIFERATION OF FIBROBLASTS IN HUMAN AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cystic tubule enlargement and expansion of the interstitium associa ted with fibrosis. Our previous studies have analyzed the increased pr oliferation of cystic epithelial cells and this study examines the bas is of increased proliferation of interstitial fibroblasts associated w ith ADPKD disease progression. ADPKD fibroblasts show phenotypic alter ations in vitro, have acquired the capacity to grow in soft agar, and show an increased mitogenic response to a variety of growth factors pa rticularly acidic FGF (aFGF). ELISA, Western immunoblot analysis, and immunocytochemistry showed increased aFGF content in ADPKD tissues and fibroblasts in culture, and aFGF was secreted into the extracellular matrix and conditioned medium, respectively. No alterations in aFGF re ceptor number were found, but Scatchard analysis of I-125-aFGF binding suggested an increased affinity of binding to the low affinity recept or, and covalent cross-linking analysis suggested the presence of nove l putative receptors (120 kDa) in ADPKD fibroblasts. Signaling abnorma lities were found, since aFGF incubation resulted in the tyrosine phos phorylation of additional substrates, more rapidly and for a more sust ained duration in ADPKD fibroblasts than in normal fibroblasts. These findings suggest an important role for acidic FGF in the hyperprolifer ation of interstitial fibroblasts associated with disease progression in human ADPKD. (C) 1997 Academic Press.