AUTOCRINE, ENDOCRINE AND PARACRINE REGULATION OF GROWTH ABNORMALITIESIN AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE

Genetic polycystic kidney disease (ADPKD) is an autosomal dominant tra it in man, the phenotypic expression of which is characterized by enor mous cystic enlargement of renal tubules. Since this is, in part, a re sult of aberrant epithelial cell proliferation, the nature or this def ect has been characterized by comparison of growth factor action on de fined epithelial primary monolayer cultures derived from individually microdissected normal human renal proximal and distal tubules and ADPK D cyst-lining epithelia. Mitogenic assays showed an increased sensitiv ity of ADPKD epithelia to stimulation by the combination of the endocr ine factors hydrocortisone (dexamethasone) and insulin, and Northern a nalysis suggested increased levels of insulin receptor steady state mR NA. The most potent, single mitogen was epidermal growth factor (EGF), and hypersensitivity to EGF in ADPKD epithelia was correlated with in creased mRNA levels for EGF receptor in ADPKD kidneys. The localizatio n in vivo of EGF immunoreactivity in ADPKD cyst-lining epithelia and i n (apical) cyst fluids and the demonstration of EGF-receptor immunosta ining and specific [I-125]EGF binding to apical cell surfaces suggeste d an autocrine mechanism of growth stimulation by EGF in ADPKD epithel ia. Transforming growth factor beta was an inhibitor of normal renal t ubule proliferation but was unable to completely inhibit EGF stimulati on in ADPKD cultures. Platelet-derived growth factor (PDGF) immunoreac tivity 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.