Antibiotics and renal branching morphogenesis: Comparison of toxicities

Abstract

Background:Many premature born neonates receive antibiotic drugs to treat infections, which are applied during active nephrogenesis. We studied the impact of clinical concentrations of gentamicin and alternatives, ceftazidime and meropenem, on ureteric branching. Methods:Mice metanephroi were dissected at embryonic day 13 and cultured in media with or without various concentrations of gentamicin, ceftazidime, or meropenem. Zero and 24 h kidney size were assessed by surface area measurements, and the ureteric tree was visualized by whole mount staining and confocal microscopy. Branching was evaluated by counting and gene expression levels of Wt1, Sox9, Bmp7, Fgf8, and Gdnf were investigated. Results:A concentration of 2,000 μmol/l ceftazidime impaired ureteric development. In addition, a 4.5-fold and a 2.5-fold downregulation was noted in Fgf8 and Gdnf, respectively. No adverse effects were noted after gentamicin or meropenem treatment. No relationship was noted between surface area expansion and ureteric bud formation, but surface area at explantation related to bud count after 24 h of culture. Conclusion:Ceftazidime, but not gentamicin or meropenem reduced ureteric branching in mice and suggest a role for Fgf8 and Gdnf in its mechanism. Metanephros surface area measurements can be used to reduce intra- and inter-litter variation.