Background: Previous studies have linked a low protein maternal diet with hypertension in adult offspring, and have suggested that impaired kidney development may be an important predisposing factor. This study aims to identify the molecular and structural changes that explain the decline in function.
Methods: Pregnant ewes were fed either a control diet providing adequate dietary protein (control protein (CP); n=15), or a low protein diet during early gestation (low protein early (LPE); n=17) or late gestation (low protein late (LPL); n=6). At day 65 gestation 9 CP and 10 LPE sheep were euthanised and fetal kidneys collected. The remainder continued to term and at 2 years of age in vivo renography was carried out on the overweight offspring before they were euthanised. Kidney sections were stained using standard DAB immunohistochemical methods or TUNEL staining, and the results analysed using Image Pro. Nephron number was estimated stereologically, mRNA by QPCR.
Results: Renography indicated reduced renal function in LPE versus CP and LPL groups associated with microalbuminuria, assessed by urinalysis. There were no significant morphological differences, nor was mean glomerular area different between groups. Nephron number was reduced by ~15% in the adult LPE group. In the fetal kidneys, renal apoptosis was greater in LPE group and VEGFA mRNA and protein were reduced. In contrast, in adult LPE kidneys, expression of VEGFA and its receptors VEGFR1 and VEGFR2 was increased along with increased VEGFA protein. For all results P<0.05.
Conclusions: This study suggests that protein restriction during early, but not late, pregnancy (i.e. during rapid nephrogenesis) affects normal fetal kidney development and leads to reduced function in the overweight adult offspring. The VEGFA pathway likely plays a key role in this process.