Blunted Sodium Excretion in Response to a Saline Load in 5 Year Old Female Sheep Following Fetal Uninephrectomy

Abstract

Previously, we have shown that fetal uninephrectomy (uni-x) causes hypertension in female sheep by 2 years of age. Whilst the hypertension was not exacerbated by 5 years of age, these uni-x sheep had greater reductions in renal blood flow (RBF). To further explore these early indications of a decline in renal function, we investigated the renal response to a saline load (25 ml/kg/40 min) in 5-year old female uni-x and sham sheep. Basal mean arterial pressure was ∼15 mmHg greater (PGroup<0.001), and sodium excretion (∼50%), glomerular filtration rate (∼30%, GFR) and RBF (∼40%) were all significantly lower (PGroup<0.01) in uni-x compared to sham animals. In response to saline loading, sodium excretion increased significantly in both groups (PTime<0.001), however this response was blunted in uni-x sheep (PGroupxTime<0.01). This was accompanied with an attenuated increase in GFR and fractional sodium excretion (both PGroupxTime<0.05), and reduced activation of the renin-angiotensin system (both P<0.05), as compared to the sham group. The reduction in sodium excretion was associated with up-regulations in the renal gene expression of NHE3 and Na+/K+ ATPase α and β subunits in the kidney cortex of the uni-x compared to the sham animals (P<0.05). Notably, neither group completely excreted the saline load within the recovery period, but the uni-x retained a higher percentage of the total volume (uni-x: 48±7%; sham: 22±9%, P<0.05). In conclusion, a reduced ability to efficiently regulate extracellular fluid homeostasis is evident in female sheep at 5 years of age, which was exacerbated in animals born with a congenital nephron deficit. Whilst there was no overt exacerbation of hypertension and renal insufficiency with age in the uni-x sheep, these animals may be more vulnerable to secondary renal insults.

Improvement in Renal Hemodynamics following Combined Angiotensin II Infusion and AT1R Blockade in Aged Female Sheep following Fetal Unilateral Nephrectomy

“…Total kidney to body weight ratio (g/kg): sham; 2.2±0.1, uni-x; 2.1±0.2). These data for birth weight and growth and kidney weights for these animals have been previously reported [28], [37].…”

“…However, studies in our model showed that 6 month old low-renin hypertensive, uni-x male sheep had significantly lower levels of renal renin and AngII content together with reduced renal gene expression of AT1R and AT2R compared to sham [22]. Recently, in response to an acute period of volume expansion via 0.9% saline loading (25 ml/kg/40 mins) we observed a blunted decrease in plasma renin activity (PRA) in 5 year old low-renin hypertensive female uni-x sheep [28]. The reasons for the attenuated decrease in PRA in response to volume expansion in the uni-x females maybe simply due to the already low basal PRA [28], however based on the aforementioned studies an up-regulation of the intra-renal RAS as observed in other low renin models of hypertension may also be an underlying mechanism.…”

“…Recently, in response to an acute period of volume expansion via 0.9% saline loading (25 ml/kg/40 mins) we observed a blunted decrease in plasma renin activity (PRA) in 5 year old low-renin hypertensive female uni-x sheep [28]. The reasons for the attenuated decrease in PRA in response to volume expansion in the uni-x females maybe simply due to the already low basal PRA [28], however based on the aforementioned studies an up-regulation of the intra-renal RAS as observed in other low renin models of hypertension may also be an underlying mechanism. Therefore, we hypothesised that these aged uni-x female sheep with low-renin hypertension may have an increase in expression and function of components of intra-renal RAS.…”

Role of the kidney in the fetal programming of adult cardiovascular disease: an update

“…Furthermore, we have also demonstrated these young uni-nephrectomised sheep have a reduced ability to excrete a saline load [51 ]. These studies demonstrate that sheep born with a congenital nephron deficit cannot tightly match sodium excretion to intake to maintain extracellular fluid homeostasis and this contributes to increased blood pressure and cardiac dysfunction in early adulthood [49,51 ]. Thus there is strong evidence that renal tubular handling of sodium is disturbed in the setting of a low nephron endowment.…”

“…This will lead to tubular growth/lengthening [45] and alteration in the number or function of the ion channels/transporters in the tubule thereby contributing to the programming of hypertension. To date changes in the gene expression of sodium, calcium and water channels have been documented in several models of programmed hypertension [46][47][48][49]50 ], but as expression levels often do not indicate functional activity the impact of these adaptations require further study in programming models.…”