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Published on: October 21, 2015
Effects of dexamethasone exposure on rat metanephric development: in vitro and in vivo studies
Reetu R Singh1, Karen M Moritz, John F Bertram
1Dept. of Anatomy and Cell Biology, Monash University, Clayton, Victoria 3800, Australia.
Abstract:
Maternal administration of dexamethasone (DEX) for 48 h early in rat kidney development results in offspring with a reduced nephron endowment. However, the mechanism through which DEX inhibits nephrogenesis is unknown. In this study, we hypothesized that DEX may indirectly inhibit nephrogenesis by inhibiting ureteric branching morphogenesis. Whole metanephroi from embryonic day 14.5 (E14.5) rat embryos were cultured in the presence of DEX. DEX (10(-5) M) exposure for 2 days significantly inhibited ureteric branching compared with metanephroi grown in control media or DEX (10(-7) M). Culturing metanephroi for a further 3 days (in control media only) reduced total glomerular number in metanephroi previously exposed to DEX (10(-5) M) or (10(-7) M) compared with control cultures. Expression of genes known to regulate ureteric branching morphogenesis was determined by real-time PCR in metanephroi after 2 days in culture. DEX exposure in vitro decreased expression of glial cell line-derived neurotrophic factor (GDNF) and increased expression of bone morphogenetic protein-4 (BMP-4) and transforming growth factor-beta1 (TGF-beta1). Similar gene expression changes were found in E16.5 metanephroi in which the dam had been exposed to 2 days of DEX (0.2 mg.kg(-1).day(-1)) at E14.5/15.5 in vivo. However, in kidneys collected at E20.5 after in vivo exposure for 2 days, GDNF expression was increased and BMP-4 and TGF-beta1 expression decreased suggesting a biphasic response in gene expression to DEX exposure. These results show for the first time that inhibition of ureteric branching morphogenesis may be a key mechanism through which DEX exposure results in a reduced nephron endowment.
Insights
Maternal dexamethasone (DEX) exposure reduces offspring nephron number by inhibiting ureteric branching, a key process in kidney development. This study reveals DEX alters gene expression, impacting kidney formation and potentially leading to long-term health issues.
Area of Science:
- Developmental biology
- Nephrology
- Pharmacology
Background:
- Maternal dexamethasone (DEX) administration early in rat kidney development leads to reduced nephron endowment in offspring.
- The precise mechanism by which DEX inhibits nephrogenesis remains largely unknown.
Purpose of the Study:
- To investigate the hypothesis that DEX indirectly inhibits nephrogenesis by impairing ureteric branching morphogenesis.
- To elucidate the molecular mechanisms underlying DEX-induced nephron deficits.
Main Methods:
- Organ culture of embryonic rat metanephroi with DEX exposure.
- Assessment of ureteric branching and glomerular number.
- Real-time PCR analysis of gene expression (GDNF, BMP-4, TGF-beta1) in response to DEX in vitro and in vivo.
Main Results:
- DEX exposure significantly inhibited ureteric branching and reduced the total glomerular number in cultured metanephroi.
- In vitro and in vivo DEX exposure altered the expression of key genes regulating ureteric branching, including GDNF, BMP-4, and TGF-beta1.
- A biphasic gene expression response to DEX was observed in vivo, with initial decreases followed by increases in specific gene expressions.
Conclusions:
- Inhibition of ureteric branching morphogenesis is identified as a primary mechanism through which maternal DEX exposure reduces nephron endowment.
- DEX-induced alterations in GDNF, BMP-4, and TGF-beta1 expression contribute to impaired kidney development.
- These findings highlight the critical impact of prenatal DEX exposure on kidney development and nephron formation.
