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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Maternal dexamethasone treatment at midgestation reduces nephron number and alters renal gene expression in the fetal spiny mouse

¹Department of Physiology and ²Department of Anatomy and Cell Biology, Monash University, Clayton, Australia

Submitted 9 July 2006 ; accepted in final form 30 August 2006

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 before the formation of glomeruli would result in adult hypertensive offspring with fewer nephrons. Furthermore, we hypothesized that this nephron deficit would result from changes in expression of genes involved in branching morphogenesis. Osmotic pumps implanted in pregnant spiny mice at midgestation (day 20) delivered dexamethasone (dex; 125 µg/kg) or saline for 60 h. Females were killed at day 23 of gestation and kidneys were frozen for real-time PCR analysis or allowed to deliver their offspring. At 20 wk of age, blood pressure was measured in the offspring for 1 wk before nephron number was determined using unbiased stereology. Males and females exposed to dex had significantly fewer nephrons (male: saline: 7,870 ± 27, dex: 6,878 ± 173; female: saline: 7,526 ± 62, dex: 5,886 ± 382; P < 0.001) compared with controls. Dex had no effect on basal blood pressure. Fetal kidneys collected at day 23 of gestation from 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 with saline 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.

BMP4; TGF-₁; gremlin; stereology; Acomys cahirinus; fetal programming

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