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1 Physiology, Monash University, Clayton, Victoria, Australia
2 Anatomy and Cell Biology, Monash University, Clayton, Victoria, Australia
* To whom correspondence should be addressed. E-mail: hayley.dickinson{at}med.monash.edu.au.
We investigated the effects of maternal glucocorticoid exposure in the spiny mouse - a precocial species with a relatively long gestation, few offspring and in which nephrogenesis is complete before birth. We hypothesized that exposure of the fetus to glucocorticoids prior to the formation of glomeruli, would result in adult hypertensive offspring with fewer nephrons. Further, we hypothesised that this nephron deficit would result from changes in expression of genes involved in branching morphogenesis. Osmotic pumps implanted in pregnant spiny mice at mid-gestation (day 20) delivered dexamethasone (dex, 125µg/kg) or saline for 60h. Females were killed at day 23 of gestation and kidneys frozen for real-time PCR analysis or allowed to deliver their offspring. At 20 weeks of age, blood pressure was measured in the offspring for 1 week before nephron number determined. Males and females exposed to dex had fewer nephrons (male; sal: 7870±27, dex: 6878±173, female; sal: 7526±162, dex: 5886±382; p<0.001) compared to controls. Dex had no effect on basal blood pressure. Kidneys from fetuses of dex-exposed mothers showed increased mRNA expression of BMP4 (p<0.05), TGF
1 (p<0.05) genes known to inhibit branching morphogenesis and gremlin (p<0.01), an antagonist of BMP4, compared to sal controls.
This study shows for the first time an upregulation of branching morphogenic genes in the fetal kidney in a model of excess maternal glucocorticoids that leads to a nephron deficit in the adult. This study also provides evidence that a reduced nephron number does not necessarily lead to development of hypertension.
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