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

Autosomal dominant polycystic kidney disease (ADPKD) is the most commo n entity of cystic diseases of the kidney leading to end-stage renal i nsufficiency. 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 signif icance of altered expression and deposition of ECM glycoproteins for h uman ADPKD at molecular levels fresh-frozen tissue from ADPKD kidneys, fetal kidneys and normal adult kidneys were comparatively tested by i mmunohistochemistry for the presence of multifunctional ECM glycoprote ins undulin, tenascin and fibronectin, interstitial collagen types I, III and VI and intrinsic basement membrane components laminin and coll agen type IV using monoclonal antibodies and polyclonal antisera. Stud ies were especially focused on ECM glycoproteins undulin and tenascin which in connection with interstitial collagens and fibronectin have s pecific structural and functional roles in tissue development and diff erentiation. Cultures of cyst-lining epithelial cells from two polycys tic kidneys and autologous fibroblasts were investigated in vitro. By Northern blot analysis mRNA levels of undulin, tenascin and the ECM-re gulating growth factor transforming growth factor-beta1 (TGF-beta1) we re investigated. A strong increase of fibrogenesis was demonstrated in tissue architecture of polycystic kidneys. Immunohistochemically sube pithelial fibrous tissue of cyst walls in ADPKD kidneys showed strong coexpression of both undulin and tenascin with marked intensity adjace nt to cyst-lining epithelium. In contrast the normal adult human kidne y and developmental stages of the fetal kidney showed expression patte rns of undulin and tenascin which were significantly different. Expres sion of interstitial collagens I, III and VI and fibronectin reflected the overall increase of fibrogenesis indicating that in particular in teractions with collagens to trigger organization of tissue architectu re are abnormal. In vitro cyst-lining epithelial cells showed abundant TGF-beta1 mRNA by Northern blot analysis. Tenascin transcripts were d etected both in fibroblasts and in cocultures of cyst-lining epithelia and autologous fibroblasts in vitro. Undulin transcripts were not det ectable under identical culture conditions, which did not yet represen t 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.