Uteroplacental insufficiency causes a nephron deficit, modest renal insufficiency but no hypertension with ageing in female rats

Abstract

In rats, uteroplacental insufficiency induced by uterine vessel ligation restricts fetal growth and impairs mammary development compromising postnatal growth. In male offspring, this results in a nephron deficit and hypertension which can be reversed by improving lactation and postnatal growth. Here, growth, blood pressure and nephron endowment in female offspring from mothers which underwent bilateral uterine vessel ligation (Restricted) on day 18 of pregnancy were examined. Sham surgery (Control) and a reduced litter group (Reduced at birth to 5, equivalent to Restricted group) were used as controls. Offspring (Control, Reduced, Restricted) were cross-fostered on postnatal day 1 onto a Control (normal lactation) or Restricted (impaired lactation) mother. Restricted-on-Restricted offspring were born small but were of similar weight to Control-on-Control by postnatal day 35. Blood pressure was not different between groups at 8, 12 or 20 weeks of age. Glomerular number was reduced in Restricted-on-Restricted offspring at 6 months without glomerular hypertrophy. Cross-fostering a Restricted pup onto a Control dam resulted in a glomerular number intermediate between Control-on-Control and Restricted-on-Restricted. Blood pressure, along with renal function, morphology and mRNA expression, was examined in Control-on-Control and Restricted-on-Restricted females at 18 months. Restricted-on-Restricted offspring did not become hypertensive but developed glomerular hypertrophy by 18 months. They had elevated plasma creatinine and alterations in renal mRNA expression of transforming growth factor-beta(1), collagen IV (alpha1) and matrix matelloproteinase-9. This suggests that perinatally growth restricted female offspring may be susceptible to onset of renal injury and renal insufficiency with ageing in the absence of concomitant hypertension.

Figure 1. Total glomerular number, individual, total glomerular volume and plasma creatinine

Total glomerular number, indicative of nephron number at 6 months (A, left) and 18 months (E, right). Individual glomerular volume (B) at 6 months and at 18 months (F) along with total glomerular volume at 6 months (C) and 18 months of age (G). Data are expressed as means ±s.e.m. (n= 4–6). Significant differences (P < 0.05) across the groups are indicated by different letters for example a is different from b. *P < 0.05 between groups.

Figure 2. Markers of renal damage at 18 months

Relative renal gene expression of TGF-β₁ (A), collagen I (α1) (B), collagen IV (α1) (C), MMP-2 (D), MMP-9 (E) and TIMP-1 (F) in the kidney at 18 months of age in Control-on-Control and Restricted-on-Restricted females. Data are expressed as means ±s.e.m. (n= 9). Significant differences (P < 0.05) between the groups are indicated by *.