title: Modification of the epidermal growth factor response by ammonia in renal cell hypertrophy.
abstract: Epidermal growth factor (EGF) causes proliferation in renal tubular cells but, when it is combined with transforming growth factor-beta1, it causes hypertrophy by a mechanism that requires the activity of the retinoblastoma family of proteins. In contrast, ammonia causes hypertrophy by decreasing lysosomal proteolysis; in some cell types, it also decreases cellular proliferation. These studies were designed to determine whether ammonia, like transforming growth factor-beta1, could convert EGF-induced hyperplasia to hypertrophy. Cultured NRK-52E cells were incubated with EGF and/or ammonia and the protein/DNA ratio was measured, as a marker of hypertrophy. Addition of ammonia to EGF-treated NRK-52E cells converted EGF-induced hyperplasia to hypertrophy, because of a decrease in DNA synthesis. The mechanism involved no change in EGF-induced protein synthesis. Inhibition of lysosomal function with a proton pump inhibitor or lysosomal protease inhibitors also converted the response of EGF-treated cells to hypertrophy. Expression of the human papilloma virus 16 E7 protein (which inactivates all members of the retinoblastoma family) prevented ammonia from converting EGF-induced hyperplasia to hypertrophy. It is concluded that ammonia converts EGF-induced hyperplasia to hypertrophy by a mechanism that involves suppression of lysosomal function and this response can be blocked by inhibiting the activity of the retinoblastoma family of proteins.
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, and Atlanta Veterans Affairs Medical Center, Decatur, Georgia.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Franch
mesh_terms: D000468:Alkalies / Q000378:metabolism; D000643:Ammonium Chloride / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006965:Hyperplasia; D006984:Hypertrophy; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000494:pharmacology; D050725:Papillomavirus E7 Proteins; D051381:Rats; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors
chemical_list: D000468:Alkalies; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16; D000643:Ammonium Chloride; D004815:Epidermal Growth Factor; D004247:DNA