Transgenerational programming of fetal nephron deficits and sex-specific adult hypertension in rats

A developmental insult that restricts growth in the first generation has the potential to program disease in subsequent generations. The aim of this study was to ascertain transgenerational growth and cardio-renal effects, via the maternal line, in a rat model of utero-placental insufficiency. Bilateral uterine vessel ligation or sham surgery (offspring termed first generation; F1 Restricted and Control, respectively) was performed in WKY rats. F1 Restricted and Control females were mated with normal males to produce second generation (F2) offspring (Restricted and Control) studied from fetal (embryonic Day 20) to adult (12 months) life. F2 Restricted male and female fetuses had reduced (P<0.05) nephron number (down 15-22%) but this deficit was not sustained postnatally and levels were similar to Controls at Day 35. F2 Restricted males, but not females, developed elevated (+16mmHg, P<0.05) systolic blood pressure at 6 months of age, which was sustained to 9 months. This was not explained by alterations to intra-renal or plasma components of the renin-angiotensin system. In a rat model of utero-placental insufficiency, we report alterations to F2 kidney development and sex-specific adult hypertension. This study demonstrates that low birthweight can have far-reaching effects that extend into the next generation.