title: Renal dysfunction is associated with a reduced contribution of nitric oxide and enhanced vasoconstriction after a congenital renal mass reduction in sheep.
abstract: BACKGROUND
  Children born with reduced congenital renal mass have an increased risk of hypertension and chronic kidney disease in adulthood, although the mechanisms are poorly understood. Similar sequelae occur after 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.
  
  
  RESULTS
  In 5-year-old female uni-x and sham sheep, mean arterial pressure, glomerular filtration rate, and renal blood flow were measured before and during NO inhibition (N(ω)-nitro-l-arginine methyl ester [L-NAME]). Reactivity was assessed in resistance arteries, including renal lobar and arcuate arteries. Basal mean arterial pressure was 15 mm Hg higher and glomerular filtration rate and renal blood flow were ≈30% lower (P<0.001) in uni-x animals. L-NAME increased mean arterial pressure by ≈17 mm Hg in both groups, whereas glomerular filtration rate and renal blood flow were decreased less in uni-x sheep (PInteraction<0.01). Endothelial NO synthase and Ser-1177-phosphorylated endothelial NO synthase protein levels were upregulated 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 cyclooxygenase-1 and -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 after congenital renal mass reduction is associated with impaired regulation of renal hemodynamics by NO. Reductions in renal blood flow and glomerular filtration rate are underpinned by impaired basal NO contribution, endothelial dysfunction, and enhanced vascular responsiveness to sympathetic nerve stimulation.
authors.affiliation: From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.).
authors.forename: Yugeesh R
authors.initials: YR
authors.lastname: Lankadeva
authors.affiliation: From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.).
authors.forename: Reetu R
authors.initials: RR
authors.lastname: Singh
authors.affiliation: From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.).
authors.forename: Karen M
authors.initials: KM
authors.lastname: Moritz
authors.affiliation: From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.).
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.affiliation: From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.).
authors.forename: Kate M
authors.initials: KM
authors.lastname: Denton
authors.affiliation: From the Department of Physiology (Y.R.L., R.R.S., H.C.P., K.M.D., M.T.) and Department of Anatomy and Developmental Biology (R.R.S.), Monash University, Victoria, Australia; and School of Biomedical Sciences, University of Queensland, St. Lucia, Australia (R.R.S., K.M.M.). Marianne.Tare@monash.edu.
authors.forename: Marianne
authors.initials: M
authors.lastname: Tare
mesh_terms: D000818:Animals; D005260:Female; D007668:Kidney / Q000002:abnormalities* / Q000502:physiology / Q000601:surgery; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D012756:Sheep; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D009569:Nitric Oxide
keywords: arteries; endothelium-derived relaxing factors; hypertension; kidney; nitric oxide