Increased cardiovascular and renal risk is associated with low nephron endowment in aged females: an ovine model of fetal unilateral nephrectomy

Abstract

Previously we have shown that ovariectomised (OVX) female sheep have reduced renal function and elevated blood pressure from 6 months of age following fetal uninephrectomy (uni-x) at 100 days of gestation (term = 150 days). In the current study we examined if in intact female sheep the onset of decline in renal function and elevation in blood pressure was prevented. Studies were performed at 1 year, 2 and 5 years of age. Following fetal uni-x at 100 days, intact female sheep had ~30% reduction in glomerular filtration rate (GFR) at 1 year, which did not exacerbate with age (P(treatment) = 0.0001, P(age) = 0.7). In contrast renal blood flow was similar between the treatment groups at 1 year of age but had declined in the uni-x animals at 5 years of age (P(treatment × age) = 0.046). Interestingly, intact uni-x sheep did not develop elevations in arterial pressure until 2 years of age. Furthermore, uni-x animals had a similar capacity to respond to a cardiac challenge at 1 year and 2 years of age, however, cardiac functional reserve was significantly reduced compared to sham group at 5 years of age. Uni-x animals exhibited an increase in left ventricular dimensions at 5 years of age compared to the sham animals and compared to 2 years of age (P(treatment)<0.001, P(treatment × age)<0.001). In conclusion, the onset of renal dysfunction preceded the onset of hypertension in intact female uni-x sheep. Furthermore, this study showed that the intact females are protected from the impact of a reduced nephron endowment on cardiovascular health early in life as opposed to our findings in young male sheep and OVX uni-x female sheep. However, with ageing this protection is lost as evidenced by presence of left ventricular hypertrophy and impaired cardiac function in 5 year old uni-x female sheep.

Figure 1. Plasma renin activity (PRA) in sham and uni-x animals (n = 5 in each group) at 1 year, 2 and 5 years of age.

Values are from two-way repeated ANOVA and expressed as mean ± SEM. Sham; clear bars, uni-x; dark bars.

Figure 2. Basal cardiovascular 24 hour cardiovascular profile in sham-operated and uni-x female sheep at 1 year, 2 and 5 years of age.

(A) Mean arterial pressure, MAP (B) cardiac output, CO (C) Total peripheral resistance, TPR, (D) Heart rate, (E) Stroke volume, SV and (F) blood volume. Values are from two-way repeated ANOVA and expressed as mean ± SEM. Sham (n = 5); clear bars, uni-x (n = 5); dark bars. *P<0.05, **P<0.01, ***P<0.001 as compared to sham group from post-hoc analysis.

Figure 3. Cardiovascular response to dobutamine challenge in sham operated and uni-x female sheep at 1 year, 2 and 5 years of age following fetal unilateral nephrectomy at 100 d gestation.

Cardiac functional reserve (CO _max−0) is presented as maximal change in cardiac output (CO) compared to baseline (0). Values are from two-way repeated ANOVA and expressed as mean ± SEM. Sham (n = 5); clear bars, uni-x (n = 5); dark bars. **P<0.01 as compared to sham group at 2 years of age from post-hoc analysis. ##P<0.01 as compared to uni-x group values at 1 and 2 years of age from post-hoc analysis.

Figure 4. Photomicrographs of representative heart sections (5 µm paraffin sections) of female sheep at 5 years of age showing areas of collagen deposition (in pink) (A) sham (B) section from a uni-x heart showing significant collagen deposition (C) collagen content expressed as percentage of total area of cardiac tissue analysed.

(D) Correlation between collagen content and percentage fractional shortening. Values are mean ± SEM. Sham (n = 5); clear circles, uni-x (n = 5); dark circles.