Renal Dysfunction is Associated with a Reduced Contribution of Nitric Oxide and Enhanced Vasoconstriction Following a Congenital Renal Mass Reduction in Sheep
Background—Children born with reduced congenital renal mass have increased risk of hypertension and chronic kidney disease in adulthood, though mechanisms are poorly understood. Similar sequelae occur following fetal uninephrectomy (uni-x) in sheep leading to a 30% nephron deficit. We hypothesized that renal dysfunction is underpinned by a reduced contribution of nitric oxide (NO) and vascular dysfunction in uni-x sheep.
Methods and Results—In 5-year old female uni-x and sham sheep, mean arterial pressure (MAP), glomerular filtration rate (GFR) and renal blood flow (RBF) were measured before and during NO inhibition (L-NAME). Reactivity was assessed in resistance arteries including renal lobar and arcuate arteries. Basal MAP was 15mmHg higher, GFR and RBF ~30% lower (P<0.001) in uni-x animals. L-NAME increased MAP by ~17 mmHg in both groups, whereas, GFR and RBF decreased less in uni-x sheep (PInteraction<0.01). Endothelial NO synthase (eNOS) and Ser-1177 phosphorylated eNOS protein levels were up-regulated in renal cortex of uni-x sheep (P<0.05). Lobar arteries of uni-x sheep had enhanced responsiveness to phenylephrine and nitrotyrosine staining and reduced sensitivity to endothelial stimulation. Vasodilator prostanoid contribution to endothelium-dependent relaxation was reduced in lobar arteries of uni-x sheep, accompanied by reduced COX-1 and COX-2 gene expression (P<0.05). Neurovascular constriction was enhanced ~1.5-fold in renal arteries of uni-x sheep (P<0.05).
Conclusions—Renal dysfunction following congenital renal mass reduction is associated with impaired regulation of renal hemodynamics by NO. Reductions in RBF and GFR are underpinned by impaired basal NO contribution, endothelial dysfunction and enhanced vascular responsiveness to sympathetic nerve stimulation.
- Received October 24, 2014.
- Accepted October 24, 2014.