Protective role of female gender in programmed accelerated renal aging in the rat

Abstract

The aging kidney exhibits a progressive decline in glomerular filtration rate, accompanied by inflammatory and oxidative damage. We hypothesized that accelerated, age-related progression of renal injury is ovarian hormones-dependant. To address this we used an established model of developmentally programmed accelerated renal aging in the rat, superimposed by ovariectomy to assess interactions between ovarian hormones and the aging process. Under our experimental conditions, we found that kidney function worsens with age, that is GFR reduces over 18 month analyzed time-course and this was worsened by fetal exposure to maternal low-protein diet and absence of estrogen. Reduction in GFR was followed by increases in albuminuria, proteinuria, inflammatory markers, and tissue carbonyls, all suggesting inflammatory response and oxidative stress. This was associated with changes in AGTR2 expression which was greater at 18 months of age compared to earlier time points, but in MLP offspring only. Our studies show an influence of ovarian hormones on programmed accelerated renal aging and the AGTR2 across the lifespan. The main findings are that ovariectomy is a risk factor for increased aging-related renal injury and that this and oxidative damage might be related to changes in AGTR2 expression.

Developmental Programming of Hypertension

“…As highlighted above, numerous models of developmental programming report a sex difference in blood pressure (9, 24, 26, 27, 28) with onset of increased CV risk delayed in females (24, 25, 29, 30). Although the importance of endothelin ( ET-1 ) as a potential contributor to the pathogenesis of hypertension and increased CV risk following a fetal insult has undergone limited investigation, recent studies published in Hypertension indicate that the ET-1 system may contribute to sex differences in increased CV risk that has its origins in early life.…”

“…Yet, female offspring exposed to an insult during fetal life do not remain protected against an increase in blood pressure in later life (25, 29). Previous studies addressing the importance of the renal nerves and SNA in the developmental programming of hypertension involve studies performed in male offspring (10, 11, 17, 23).…”

Gender differences in developmental programming of cardiovascular diseases

“…This model which mimics chronic undernutrition in regions that suffer from extreme malnutrition in developing countries is useful for studying the mechanisms by which early growth patterns are related to adult cardiovascular disease. However, the developmental programming effects of a maternal low protein diet vary greatly due to differences in dietary components of the protein restricted diets [77–78] and the method used for measurement of BP [6–7,79–80]. Additionally, the severity of the restriction of protein in the maternal diet also results in sex-specific programming of CV risk [6–7].…”

“…Joles et al reported that, fetal exposure to low protein during gestation increased renal injury in the aging male kidney [81] (Figure 3). Yet, an additional study indicated that female offspring exposed to moderate maternal protein restriction during fetal life were protected against the accelerated development of renal injury [79]. Removal of the ovarian hormones accelerated age-related reductions in GFR and worsened albuminuria in female low protein offspring [79] (Figure 4) indicating that similar to the model of placental insufficiency, ovarian hormones played a protective role in the programming of chronic health in female offspring.…”

“…Yet, an additional study indicated that female offspring exposed to moderate maternal protein restriction during fetal life were protected against the accelerated development of renal injury [79]. Removal of the ovarian hormones accelerated age-related reductions in GFR and worsened albuminuria in female low protein offspring [79] (Figure 4) indicating that similar to the model of placental insufficiency, ovarian hormones played a protective role in the programming of chronic health in female offspring. However, BP was increased in both male and female offspring exposed to a more severe reduction in protein intake within the maternal diet (6% versus 18% reduction) [77].…”