Impaired ability to modulate glomerular filtration rate in aged female sheep following fetal uninephrectomy

Abstract

Fetal uninephrectomy (uni‐x) results in hypertension at a later age in female than male sheep. We hypothesized that dysregulation of tubular sodium handling contributes to the reduced ability to regulate extracellular fluid (ECF) homeostasis in older females born with a congenital nephron deficit. Following renal excretory balance studies, the response to inhibition of the Na+K+2Cl− cotransporter with furosemide (0.5 mg/kg bolus + 1 mg/kg per hour, i.v) or vehicle treatment was examined in conscious 5‐year‐old female uni‐x (n = 7) and sham (n = 7) sheep. Balance studies in meal‐fed sheep demonstrated that while average 24 h sodium excretion over 6 days was not different between the groups, the daily variation in sodium excretion was significantly greater in uni‐x compared to sham sheep (31 ± 4% vs. 12 ± 2%; P < 0.001). Basal plasma renin activity (PRA) and renal cortical cyclooxygenase‐2 (COX‐2) gene expression were lower in uni‐x sheep (both, P < 0.01). The increases in glomerular filtration rate (GFR) and renal blood flow observed in sham sheep in response to furosemide were significantly attenuated in uni‐x sheep (both PGROUP×TREAT < 0.05). However, fractional sodium excretion increased by a greater extent in the uni‐x (4.4 ± 1.0%) as compared to the sham sheep (2.0 ± 0.4%; PGROUP×TIME < 0.05) in response to furosemide. In conclusion, fetal uni‐x was associated with altered renal sodium handling and hypertension in aged females. The impaired ability to modulate PRA and GFR in the adults with a congenital nephron deficit may reduce the capacity of the kidney to respond to gains or losses in ECF to maintain a stable internal environment.

Physiological parameter values for physiologically based pharmacokinetic models in food‐producing animals. Part III: Sheep and goat

“…A previous PBPK modeling study of penicillin G reported that a lower urine elimination rate in heavy sows would lead to a longer withdrawal interval than that from market‐age swine (Li, Mainquist‐Whigham, et al., 2019 ). Similarly, the declined renal blood flow and decreased GFR were reported in aged female sheep (Lankadeva et al., 2014 ).…”

Loss of a kidney during fetal life: long-term consequences and lessons learned

“…2). Similar fluctuations in daily sodium excretion have also been observed in female uni-x sheep at 5 yr of age (45). Thus renal function is impaired in animal models of SFK and is associated with hypertension, when the loss occurs during the nephrogenic period.…”

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