COEXPRESSION OF EXTRACELLULAR-MATRIX GLYCOPROTEINS UNDULIN AND TENASCIN IN HUMAN AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE

Autosomal dominant polycystic kidney disease (ADPKD) is the most common entity of cystic diseases of the kidney leading to end-stage renal insufficiency. Changes in extracellular matrix (ECM) are regarded to be an important pathogenic factor connected with the genes assumed to be responsible for human ADPKD. In order to assess the biological significance of altered expression and deposition of ECM glycoproteins for human ADPKD at molecular levels fresh-frozen tissue from ADPKD kidneys, fetal kidneys and normal adult kidneys were comparatively tested by immunohistochemistry for the presence of multifunctional ECM glycoproteins undulin, tenascin and fibronectin, interstitial collagen types I, III and VI and intrinsic basement membrane components laminin and collagen type IV using monoclonal antibodies and polyclonal antisera. Studies were especially focused on ECM glycoproteins undulin and tenascin which in connection with interstitial collagens and fibronectin have specific structural and functional roles in tissue development and differentiation. Cultures of cyst-lining epithelial cells from two polycystic kidneys and autologous fibroblasts were investigated in vitro. By Northern blot analysis mRNA levels of undulin, tenascin and the ECM-regulating growth factor transforming growth factor-beta1 (TGF-beta1) were investigated. A strong increase of fibrogenesis was demonstrated in tissue architecture of polycystic kidneys. Immunohistochemically subepithelial fibrous tissue of cyst walls in ADPKD kidneys showed strong coexpression of both undulin and tenascin with marked intensity adjacent to cyst-lining epithelium. In contrast the normal adult human kidney and developmental stages of the fetal kidney showed expression patterns of undulin and tenascin which were significantly different. Expression of interstitial collagens I, III and VI and fibronectin reflected the overall increase of fibrogenesis indicating that in particular interactions with collagens to trigger organization of tissue architecture are abnormal. In vitro cyst-lining epithelial cells showed abundant TGF-beta1 mRNA by Northern blot analysis. Tenascin transcripts were detected both in fibroblasts and in cocultures of cyst-lining epithelia and autologous fibroblasts in vitro. Undulin transcripts were not detectable under identical culture conditions, which did not yet represent the appropriate experimental model system to imitate the particular epithelial-mesenchymal interactions leading to the expression of both ECM components in ADPKD kidneys in vivo.