Urine-concentrating defects exacerbate with age in male offspring with a low-nephron endowment

Abstract

Fetal uninephrectomy (uni-x) in male sheep at 100 days of gestation (term = 150 days) reduces overall nephron endowment without affecting birth weight. Offspring have a lower glomerular filtration rate (GFR) and elevated mean arterial pressure (MAP) at 6 mo of age. This study investigated whether this reduction in renal function was associated with impaired urine-concentrating ability at 6 mo of age and exacerbated with ageing (4 yr) and examined response to 1) nonpressor dose of exogenous arginine vasopressin (AVP; 0.2 μg·kg−1·h−1 iv) and 2) 30 h of water deprivation. Basal MAP was higher in uni-x animals at both ages, and became further elevated with age compared with the sham group (elevation in MAP with age; sham: ∼4 mmHg, uni-x: 9 mmHg, Pgroup × age < 0.01). GFR declined with ageing in both groups with the decrease being greater with age in the uni-x group (further 26%, Pgroup × age < 0.001). In response to AVP infusion, urine osmolality increased in both treatment groups; this response was significantly lower in the uni-x animals and became further reduced with ageing. Uni-x animals had reduced renal expression of vasopressin-2 receptor and aquaporin-2 at both ages ( P < 0.01). The increase in plasma AVP levels in response to dehydration was similar between the treatment groups, suggesting the urine-concentrating defect was associated with these renal gene changes rather than defects in AVP secretion. Renal insufficiency due to a low-nephron endowment increases the risk of hypertension and chronic renal disease and may incur greater vulnerability to physiological challenges such as water deprivation as observed in the uni-x animals.