Acute inhibition of the endogenous xanthine oxidase improves renal hemodynamics in hypercholesterolemic pigs

Elena Daghini, Alejandro R. Chade, James D. Krier, Daniele Versari, Amir Lerman, Lilach O Lerman

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Hypercholesterolemia (HC), a major risk factor for onset and progression of renal disease, is associated with increased oxidative stress, potentially causing endothelial dysfunction. One of the sources of superoxide anion is xanthine oxidase (XO), but its contribution to renal endothelial function in HC remains unclear. We tested the hypothesis that XO modulates renal hemodynamics and endothelial function in HC pigs. Four groups (n = 23) of female domestic pigs were studied 12 wk after either normal (n = 11) or HC diet (n = 12). Oxidative stress was assessed by plasma isoprostanes and oxidized LDL, and the XO system by plasma uric acid, urinary xanthine, and renal XO expression (by immunoblotting and immunohistochemistry). Renal hemodynamics and function were studied with electron beam-computed tomography before and after endothelium-dependent (ACh) and -independent (sodium nitroprusside) challenge, during a concurrent intrarenal infusion of either oxypurinol or saline (n = 5-6 in each group). HC showed elevated oxidative stress, higher plasma uric acid (23.8 ± 3.8 vs. 6.2 ± 0.8 μM/mM creatinine, P = 0.001), lower urinary xanthine, and greater renal XO expression compared with normal. Inhibition of XO in HC significantly improved the blunted responses to ACh of cortical perfusion (13.5 ± 12.1 and 37.2 ± 10.6%, P = 0.01 and P = not significant vs. baseline, respectively), renal blood flow, and glomerular filtration rate; restored medullary perfusion; and improved the blunted cortical perfusion response to sodium nitroprusside. This study demonstrates that the endogenous XO system is activated in swine HC. Furthermore, it suggests an important role for XO in regulation of renal hemodynamics, function, and endothelial function in experimental HC.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume290
Issue number3
DOIs
StatePublished - Mar 2006

Fingerprint

Xanthine Oxidase
Hypercholesterolemia
Swine
Hemodynamics
Kidney
Oxidative Stress
Xanthine
Perfusion
Nitroprusside
Uric Acid
Oxypurinol
Isoprostanes
Sus scrofa
X Ray Computed Tomography
Renal Circulation
Glomerular Filtration Rate
Immunoblotting
Superoxides
Endothelium
Disease Progression

Keywords

  • Endothelium
  • Oxidative stress
  • Oxypurinol
  • Uric acid

ASJC Scopus subject areas

  • Physiology

Cite this

Acute inhibition of the endogenous xanthine oxidase improves renal hemodynamics in hypercholesterolemic pigs. / Daghini, Elena; Chade, Alejandro R.; Krier, James D.; Versari, Daniele; Lerman, Amir; Lerman, Lilach O.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 290, No. 3, 03.2006.

Research output: Contribution to journalArticle

@article{09a4ad1a84214aa78dcb07cf3b46ff78,
title = "Acute inhibition of the endogenous xanthine oxidase improves renal hemodynamics in hypercholesterolemic pigs",
abstract = "Hypercholesterolemia (HC), a major risk factor for onset and progression of renal disease, is associated with increased oxidative stress, potentially causing endothelial dysfunction. One of the sources of superoxide anion is xanthine oxidase (XO), but its contribution to renal endothelial function in HC remains unclear. We tested the hypothesis that XO modulates renal hemodynamics and endothelial function in HC pigs. Four groups (n = 23) of female domestic pigs were studied 12 wk after either normal (n = 11) or HC diet (n = 12). Oxidative stress was assessed by plasma isoprostanes and oxidized LDL, and the XO system by plasma uric acid, urinary xanthine, and renal XO expression (by immunoblotting and immunohistochemistry). Renal hemodynamics and function were studied with electron beam-computed tomography before and after endothelium-dependent (ACh) and -independent (sodium nitroprusside) challenge, during a concurrent intrarenal infusion of either oxypurinol or saline (n = 5-6 in each group). HC showed elevated oxidative stress, higher plasma uric acid (23.8 ± 3.8 vs. 6.2 ± 0.8 μM/mM creatinine, P = 0.001), lower urinary xanthine, and greater renal XO expression compared with normal. Inhibition of XO in HC significantly improved the blunted responses to ACh of cortical perfusion (13.5 ± 12.1 and 37.2 ± 10.6{\%}, P = 0.01 and P = not significant vs. baseline, respectively), renal blood flow, and glomerular filtration rate; restored medullary perfusion; and improved the blunted cortical perfusion response to sodium nitroprusside. This study demonstrates that the endogenous XO system is activated in swine HC. Furthermore, it suggests an important role for XO in regulation of renal hemodynamics, function, and endothelial function in experimental HC.",
keywords = "Endothelium, Oxidative stress, Oxypurinol, Uric acid",
author = "Elena Daghini and Chade, {Alejandro R.} and Krier, {James D.} and Daniele Versari and Amir Lerman and Lerman, {Lilach O}",
year = "2006",
month = "3",
doi = "10.1152/ajpregu.00436.2005",
language = "English (US)",
volume = "290",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "3",

}

TY - JOUR

T1 - Acute inhibition of the endogenous xanthine oxidase improves renal hemodynamics in hypercholesterolemic pigs

AU - Daghini, Elena

AU - Chade, Alejandro R.

AU - Krier, James D.

AU - Versari, Daniele

AU - Lerman, Amir

AU - Lerman, Lilach O

PY - 2006/3

Y1 - 2006/3

N2 - Hypercholesterolemia (HC), a major risk factor for onset and progression of renal disease, is associated with increased oxidative stress, potentially causing endothelial dysfunction. One of the sources of superoxide anion is xanthine oxidase (XO), but its contribution to renal endothelial function in HC remains unclear. We tested the hypothesis that XO modulates renal hemodynamics and endothelial function in HC pigs. Four groups (n = 23) of female domestic pigs were studied 12 wk after either normal (n = 11) or HC diet (n = 12). Oxidative stress was assessed by plasma isoprostanes and oxidized LDL, and the XO system by plasma uric acid, urinary xanthine, and renal XO expression (by immunoblotting and immunohistochemistry). Renal hemodynamics and function were studied with electron beam-computed tomography before and after endothelium-dependent (ACh) and -independent (sodium nitroprusside) challenge, during a concurrent intrarenal infusion of either oxypurinol or saline (n = 5-6 in each group). HC showed elevated oxidative stress, higher plasma uric acid (23.8 ± 3.8 vs. 6.2 ± 0.8 μM/mM creatinine, P = 0.001), lower urinary xanthine, and greater renal XO expression compared with normal. Inhibition of XO in HC significantly improved the blunted responses to ACh of cortical perfusion (13.5 ± 12.1 and 37.2 ± 10.6%, P = 0.01 and P = not significant vs. baseline, respectively), renal blood flow, and glomerular filtration rate; restored medullary perfusion; and improved the blunted cortical perfusion response to sodium nitroprusside. This study demonstrates that the endogenous XO system is activated in swine HC. Furthermore, it suggests an important role for XO in regulation of renal hemodynamics, function, and endothelial function in experimental HC.

AB - Hypercholesterolemia (HC), a major risk factor for onset and progression of renal disease, is associated with increased oxidative stress, potentially causing endothelial dysfunction. One of the sources of superoxide anion is xanthine oxidase (XO), but its contribution to renal endothelial function in HC remains unclear. We tested the hypothesis that XO modulates renal hemodynamics and endothelial function in HC pigs. Four groups (n = 23) of female domestic pigs were studied 12 wk after either normal (n = 11) or HC diet (n = 12). Oxidative stress was assessed by plasma isoprostanes and oxidized LDL, and the XO system by plasma uric acid, urinary xanthine, and renal XO expression (by immunoblotting and immunohistochemistry). Renal hemodynamics and function were studied with electron beam-computed tomography before and after endothelium-dependent (ACh) and -independent (sodium nitroprusside) challenge, during a concurrent intrarenal infusion of either oxypurinol or saline (n = 5-6 in each group). HC showed elevated oxidative stress, higher plasma uric acid (23.8 ± 3.8 vs. 6.2 ± 0.8 μM/mM creatinine, P = 0.001), lower urinary xanthine, and greater renal XO expression compared with normal. Inhibition of XO in HC significantly improved the blunted responses to ACh of cortical perfusion (13.5 ± 12.1 and 37.2 ± 10.6%, P = 0.01 and P = not significant vs. baseline, respectively), renal blood flow, and glomerular filtration rate; restored medullary perfusion; and improved the blunted cortical perfusion response to sodium nitroprusside. This study demonstrates that the endogenous XO system is activated in swine HC. Furthermore, it suggests an important role for XO in regulation of renal hemodynamics, function, and endothelial function in experimental HC.

KW - Endothelium

KW - Oxidative stress

KW - Oxypurinol

KW - Uric acid

UR - http://www.scopus.com/inward/record.url?scp=33645409484&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645409484&partnerID=8YFLogxK

U2 - 10.1152/ajpregu.00436.2005

DO - 10.1152/ajpregu.00436.2005

M3 - Article

C2 - 16284087

AN - SCOPUS:33645409484

VL - 290

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 3

ER -