CALL FOR PAPERS Programming Normal Renal Development and Modeling Disease Pathogenesis Urine-concentrating defects exacerbate with age in male offspring with a low-nephron endowment

Singh RR, Denton KM, Bertram JF, Dowling J, Moritz KM. Urineconcentrating defects exacerbate with age in male offspring with a lownephron endowment. Am J Physiol Renal Physiol 301: F1168–F1176, 2011. First published September 14, 2011; doi:10.1152/ajprenal.00463.2011.— 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 g·kg ·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 urineconcentrating 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.