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Terminal renal failure in mice lacking transcription factor AP-2 beta


Moser,  M.
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Moser, M., Dahmen, S., Kluge, R., Gröne, H., Dahmen, J., Kunz, D., et al. (2003). Terminal renal failure in mice lacking transcription factor AP-2 beta. Laboratory Investigation, 83(4), 571-578.

Inactivation of the transcription factor AP-2beta in a genetically mixed C57BU6/129S1 mouse strain resulted in perinatal lethality as a consequence of massively enhanced apoptotic death of renal epithelial cells (Genes Dev 1997;11:19381948). Recently, we observed that the phenotype is modulated by genetic background because AP-2beta 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-2beta 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-2beta in renal tubular functions.