Being born small for gestational age reduces nephron endowment and increases cardio-renal disease risk, with males more prone to these diseases than females. This disease predisposition is not limited to the first directly exposed generation (F1) but can affect multiple ensuing generations. This study investigated if the renal dysfunction in F1 males is passed onto F2 and F3 offspring.
Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on embryonic day 18 in Wistar-Kyoto rats. F1 male offspring were mated with normal females at 5 months giving rise to F2 which were subsequently mated with normal females to generate F3. Nephron number was quantified using unbiased stereology at day 35. At 6 months of age F2 and F3 rats were placed in a metabolic cage to collect urine (albumin, protein, creatinine and electrolytes) and plasma (creatinine) was taken by tail vein to calculate estimated glomerular filtration rate (eGFR).
No changes in male or female birth weight or nephron number were observed in either generation. F2 Restricted males were heavier at 6 months with no changes in F3 weights. F2 Restricted males had reduced eGFR (-44%), urinary albumin (-53%) and protein (-32%) compared to Control. In the F3 generation, Restricted males had reduced urinary protein (-31%) and reduced sodium excretion emerged (-44%). In the Restricted females, despite no changes in F2 renal function, the F3 generation had reduced eGFR (-47%), urinary protein (-37%) and potassium handling (-29%).
This is the first study to demonstrate that the renal dysfunction associated with being born small is transmitted to two subsequent generations down the paternal line in a sex-specific fashion. The reduced urinary protein suggests enhanced uptake by the kidneys which may be a functional nephron adaptation due to the nephron deficit in F1 males to prevent protein loss.