Autocrine, endocrine and paracrine regulation of growth abnormalities in autosomal dominant polycystic kidney disease.
Genetic polycystic kidney disease (ADPKD) is an autosomal dominant trait in man, the phenotypic expression of which is characterized by enormous cystic enlargement of renal tubules. Since this is, in part, a result of aberrant epithelial cell proliferation, the nature of this defect has been characterized by comparison of growth factor action on defined epithelial primary monolayer cultures derived from individually microdissected normal human renal proximal and distal tubules and ADPKD cyst-lining epithelia. Mitogenic assays showed an increased sensitivity of ADPKD epithelia to stimulation by the combination of the endocrine factors hydrocortisone (dexamethasone) and insulin, and Northern analysis suggested increased levels of insulin receptor steady state mRNA. The most potent, single mitogen was epidermal growth factor (EGF), and hypersensitivity to EGF in ADPKD epithelia was correlated with increased mRNA levels for EGF receptor in ADPKD kidneys. The localization in vivo of EGF immunoreactivity in ADPKD cyst-lining epithelia and in (apical) cyst fluids and the demonstration of EGF-receptor immunostaining and specific [125I]EGF binding to apical cell surfaces suggested an autocrine mechanism of growth stimulation by EGF in ADPKD epithelia. Transforming growth factor beta was an inhibitor of normal renal tubule proliferation but was unable to completely inhibit EGF stimulation in ADPKD cultures. Platelet-derived growth factor (PDGF) immunoreactivity which was also seen in ADPKD cyst epithelia, was not mitogenic to ADPKD epithelia but did stimulate division in ADPKD fibroblasts in vitro. This suggested a paracrine regulation of the observed fibrosis in ADPKD.
Wilson
P D
PD
Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Du
J
J
Norman
J T
JT
D015152:Blotting, Northern; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000502:physiology; D004847:Epithelial Cells; D005455:Fluorescent Antibody Technique; D006133:Growth Substances / Q000032:analysis / Q000502:physiology*; D006728:Hormones / Q000502:physiology*; D006801:Humans; D007457:Iodine Radioisotopes; D008934:Mitogens / Q000502:physiology*; D010455:Peptides / Q000032:analysis / Q000502:physiology*; D016891:Polycystic Kidney, Autosomal Dominant / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D011869:Radioligand Assay
D006133:Growth Substances; D006728:Hormones; D007457:Iodine Radioisotopes; D008934:Mitogens; D010455:Peptides; D012333:RNA, Messenger; D004815:Epidermal Growth Factor