Impact of diet and exercise in growth restricted female rats on nephron endowment in male fetuses

Uteroplacental insufficiency impairs kidney development and programs male-onset cardiorenal disease, which can be transmitted to subsequent generations. Maternal lifestyle factors can independently influence fetal kidney development, highlighting that the lifestyle of growth-restricted females can have further influence on F2 kidney development. In this study, we examined the impact of maternal growth restriction with or without additional lifestyle factors on F2 male kidney development. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was performed on embryonic day 18 in Wistar-Kyoto rats. F1 females were fed a Chow or High-fat diet from weaning (5 weeks of age). At 16 weeks, females were randomly allocated to an exercise group: no exercise (Sedentary); exercised prior to and during pregnancy (Exercise); or exercised only during pregnancy (PregEx). Females were mated at 20 weeks, with F2 male kidneys collected (embryonic day 20). Maternal growth restriction alone reduced nephron endowment by 29%, whereas additional lifestyle factors in Restricted dams reduced nephron endowment by ∼43%. Interestingly, Exercise only in High-fat dams did not alter nephron endowment, which is likely to be attributable to significant kidney remodelling and/or enhanced resource availability. This study demonstrates that growth-restricted dams that experience multiple maternal lifestyle factors (i.e. High-fat diet and PregEx) impair the development of male F2 kidneys to a more severe extent than fetuses exposed to maternal growth restriction alone or a single maternal lifestyle factor in dams of normal birth weight (i.e. high-fat feeding or exercise alone). Importantly, positive lifestyle interventions (Exercise) in a high-fat environment compounded by adverse metabolic programming (Restriction) can be beneficial to fetal kidney development, which might prevent the transgenerational programming of cardiorenal disease.