title: Terminal renal failure in mice lacking transcription factor AP-2 beta.
abstract: Inactivation of the transcription factor AP-2 beta in a genetically mixed C57BL/6/129S1 mouse strain resulted in perinatal lethality as a consequence of massively enhanced apoptotic death of renal epithelial cells (Genes Dev 1997;11:1938-1948). Recently, we observed that the phenotype is modulated by genetic background because AP-2 beta mutant mice, backcrossed onto 129P2 background, survive approximately 2 weeks after birth, allowing for a detailed analysis of kidney function. Here we show that kidneys reveal varying amounts of cysts derived from all tubular structures (proximal and distal tubuli, collecting ducts). However, all mice died irrespective of the degree of cyst formation. Serum analysis of AP-2 beta mutant animals revealed defective tubular secretory function and ion homeostasis including severe hypocalcemia, hyperphosphatemia, and hyperuremia. Because hormonal calcium regulation was not impaired, the mice developed secondary renal hyperparathyroidism as typically observed in patients with terminal renal failure. We further demonstrate that molecular defects in the collecting duct system lead to insufficient water retention and urinary concentration. In summary, our studies reveal essential, nonredundant roles of AP-2 beta in renal tubular functions.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Sandra
authors.initials: S
authors.lastname: Dahmen
authors.forename: Reinhart
authors.initials: R
authors.lastname: Kluge
authors.forename: Hermann
authors.initials: H
authors.lastname: Gröne
authors.forename: Judith
authors.initials: J
authors.lastname: Dahmen
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kunz
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D019084:Fluorescent Antibody Technique, Indirect; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006962:Hyperparathyroidism, Secondary / Q000209:etiology / Q000235:genetics / Q000473:pathology; D017403:In Situ Hybridization; D007178:Inbreeding; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010280:Parathyroid Glands / Q000378:metabolism / Q000473:pathology; D010281:Parathyroid Hormone / Q000378:metabolism; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics / Q000473:pathology; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000378:metabolism; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; C493669:Tfap2b protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors