Aberrant epithelial cell growth in autosomal dominant polycystic kidney disease.
Renal cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) is characterized by increased epithelial cell proliferation and fluid accumulation. Using monolayer epithelial cultures derived from individually microdissected human ADPKD cysts and immunolocalization studies in vivo, the roles of matrix and growth factors in aberrant ADPKD cell proliferation have been studied. Abnormal ADPKD basement membrane ultrastructure was associated with increased turnover of 35S-labeled heparan sulfate proteoglycans (HSPG) by comparison to normal renal tubule epithelia in vitro. Mitogenic assays demonstrated significant increase in 3H-thymidine incorporation into ADPKD epithelia grown on type I and type IV collagen by comparison to normal proximal straight tubules (PST), collecting ducts, and thick ascending limbs of Henle (TAL). Proliferation on laminin or fibronectin matrices was unchanged and immunolocalization of matrix proteins was polarized and restricted to basal membranes of both ADPKD cysts and renal tubule epithelia in vivo. ADPKD epithelia in vitro were hypersensitive to the mitogenic action of epidermal growth factor (EGF) and EGF immunoreactivity was detected in ADPKD cyst lining epithelia, in cyst fluid, and in conditioned media from confluent ADPKD cultures, suggesting an autocrine mechanism of growth regulation. In addition, inhibition of epithelial proliferation by transforming growth factor-beta (TGF-beta), which was 100% in normal renal tubule epithelia, was reduced to 41% in ADPKD epithelia.
Wilson
P D
PD
Department of Physiology, UMDNJ-Robert Wood Johnson Medical School, Piscataway 08854.
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D002869:Chromosome Aberrations / Q000473:pathology*; D025063:Chromosome Disorders; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology*; D007690:Polycystic Kidney Diseases / Q000473:pathology*
D006133:Growth Substances