Renal dysfunction is associated with a reduced contribution of nitric oxide and enhanced vasoconstriction following a congenital renal mass reduction in sheep

Lankadeva, Yugeesh R., Singh, Reetu R., Moritz, Karen M., Parkington, Helena C., Denton, Kate M. and Tare, Marianne (2015) Renal dysfunction is associated with a reduced contribution of nitric oxide and enhanced vasoconstriction following a congenital renal mass reduction in sheep. Circulation, 131 3: 280-288. doi:10.1161/CIRCULATIONAHA.114.013930


Author Lankadeva, Yugeesh R.
Singh, Reetu R.
Moritz, Karen M.
Parkington, Helena C.
Denton, Kate M.
Tare, Marianne
Title Renal dysfunction is associated with a reduced contribution of nitric oxide and enhanced vasoconstriction following a congenital renal mass reduction in sheep
Journal name Circulation   Check publisher's open access policy
ISSN 1524-4539
0009-7322
Publication date 2015-01-20
Year available 2014
Sub-type Article (original research)
DOI 10.1161/CIRCULATIONAHA.114.013930
Volume 131
Issue 3
Start page 280
End page 288
Total pages 38
Place of publication Philadelphia PA, United States
Publisher Lippincott Williams & Wilkins
Collection year 2015
Language eng
Formatted 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.

Methods and 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 (Nω-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.
Keyword Arteries
Endothelium-derived relaxing factors
Hypertension
Kidney
Nitric oxide
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 4 November 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
 
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