Antioxidant intervention prevents renal neovascularization in hypercholesterolemic pigs

Alejandro R. Chade, Michael D. Bentley, Xiangyang Zhu, Martin G Rodriguez-Porcel, Sara Niemeyer, Beatriz Amores-Arriaga, Claudio Napoli, Erik L. Ritman, Amir Lerman, Lilach O Lerman

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Experimental hypercholesterolemia (HC) may lead to microvascular neovascularization, but the underlying pathogenic mechanism remains unclear. We tested the hypothesis that HC-induced intra-renal neovascularization is associated with inflammation and increased oxidative stress, and would be prevented by chronic antioxidant intervention. Kidneys were excised from pigs after a 12-wk normal (n = 10) or HC diet (n = 8), or HC diet supplemented daily with antioxidant vitamins C (1 g) and E (100 IU/kg) (HC + vitamins, n = 7). Renal cortical samples were then scanned three dimensionally with micro-computed tomography, and microvessels were counted in situ. Blood and tissue samples were removed for measurements of superoxide dismutase (SOD) activity, protein expression of the NADP(H)-oxidase subunits gp91phox, p47phox, and p67phox, vascular endothelial growth factor (VEGF) levels and mRNA, VEGF receptors (Flt-1 and Flk-1), the proinflammatory transcription factor NFκB, and the oxidized LDL receptor LOX-1. Microvascular spatial density was significantly elevated in HC compared with normal kidneys but preserved in HC + vitamins. Expression of gp91phox and p67phox was decreased in HC pigs after antioxidant intervention, and SOD improved. The increased renal expression of VEGF and Flk-1 in HC was blunted in HC + vitamins, as were the significant increases in LOX-1, NFκB, and interstitial fibrosis. This study shows that renal cortical neovascularization elicited by diet-induced HC is associated with renal inflammation, fibrosis, and upregulation of VEGF and its receptor Flk-1, likely mediated by increased endogenous oxidative stress. Chronic antioxidant supplementation may preserve the kidney in HC.

Original languageEnglish (US)
Pages (from-to)1816-1825
Number of pages10
JournalJournal of the American Society of Nephrology
Volume15
Issue number7
DOIs
StatePublished - Jul 2004

Fingerprint

Hypercholesterolemia
Swine
Antioxidants
Kidney
Vitamins
Diet
Vascular Endothelial Growth Factor A
Superoxide Dismutase
Oxidized LDL Receptors
Oxidative Stress
Fibrosis
Inflammation
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor
Microvessels
NADP
Ascorbic Acid
Oxidoreductases
Transcription Factors
Up-Regulation

ASJC Scopus subject areas

  • Nephrology

Cite this

Antioxidant intervention prevents renal neovascularization in hypercholesterolemic pigs. / Chade, Alejandro R.; Bentley, Michael D.; Zhu, Xiangyang; Rodriguez-Porcel, Martin G; Niemeyer, Sara; Amores-Arriaga, Beatriz; Napoli, Claudio; Ritman, Erik L.; Lerman, Amir; Lerman, Lilach O.

In: Journal of the American Society of Nephrology, Vol. 15, No. 7, 07.2004, p. 1816-1825.

Research output: Contribution to journalArticle

Chade, Alejandro R. ; Bentley, Michael D. ; Zhu, Xiangyang ; Rodriguez-Porcel, Martin G ; Niemeyer, Sara ; Amores-Arriaga, Beatriz ; Napoli, Claudio ; Ritman, Erik L. ; Lerman, Amir ; Lerman, Lilach O. / Antioxidant intervention prevents renal neovascularization in hypercholesterolemic pigs. In: Journal of the American Society of Nephrology. 2004 ; Vol. 15, No. 7. pp. 1816-1825.
@article{a51af8cd3343430b9357bafdb7efe136,
title = "Antioxidant intervention prevents renal neovascularization in hypercholesterolemic pigs",
abstract = "Experimental hypercholesterolemia (HC) may lead to microvascular neovascularization, but the underlying pathogenic mechanism remains unclear. We tested the hypothesis that HC-induced intra-renal neovascularization is associated with inflammation and increased oxidative stress, and would be prevented by chronic antioxidant intervention. Kidneys were excised from pigs after a 12-wk normal (n = 10) or HC diet (n = 8), or HC diet supplemented daily with antioxidant vitamins C (1 g) and E (100 IU/kg) (HC + vitamins, n = 7). Renal cortical samples were then scanned three dimensionally with micro-computed tomography, and microvessels were counted in situ. Blood and tissue samples were removed for measurements of superoxide dismutase (SOD) activity, protein expression of the NADP(H)-oxidase subunits gp91phox, p47phox, and p67phox, vascular endothelial growth factor (VEGF) levels and mRNA, VEGF receptors (Flt-1 and Flk-1), the proinflammatory transcription factor NFκB, and the oxidized LDL receptor LOX-1. Microvascular spatial density was significantly elevated in HC compared with normal kidneys but preserved in HC + vitamins. Expression of gp91phox and p67phox was decreased in HC pigs after antioxidant intervention, and SOD improved. The increased renal expression of VEGF and Flk-1 in HC was blunted in HC + vitamins, as were the significant increases in LOX-1, NFκB, and interstitial fibrosis. This study shows that renal cortical neovascularization elicited by diet-induced HC is associated with renal inflammation, fibrosis, and upregulation of VEGF and its receptor Flk-1, likely mediated by increased endogenous oxidative stress. Chronic antioxidant supplementation may preserve the kidney in HC.",
author = "Chade, {Alejandro R.} and Bentley, {Michael D.} and Xiangyang Zhu and Rodriguez-Porcel, {Martin G} and Sara Niemeyer and Beatriz Amores-Arriaga and Claudio Napoli and Ritman, {Erik L.} and Amir Lerman and Lerman, {Lilach O}",
year = "2004",
month = "7",
doi = "10.1097/01.ASN.0000130428.85603.6B",
language = "English (US)",
volume = "15",
pages = "1816--1825",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "7",

}

TY - JOUR

T1 - Antioxidant intervention prevents renal neovascularization in hypercholesterolemic pigs

AU - Chade, Alejandro R.

AU - Bentley, Michael D.

AU - Zhu, Xiangyang

AU - Rodriguez-Porcel, Martin G

AU - Niemeyer, Sara

AU - Amores-Arriaga, Beatriz

AU - Napoli, Claudio

AU - Ritman, Erik L.

AU - Lerman, Amir

AU - Lerman, Lilach O

PY - 2004/7

Y1 - 2004/7

N2 - Experimental hypercholesterolemia (HC) may lead to microvascular neovascularization, but the underlying pathogenic mechanism remains unclear. We tested the hypothesis that HC-induced intra-renal neovascularization is associated with inflammation and increased oxidative stress, and would be prevented by chronic antioxidant intervention. Kidneys were excised from pigs after a 12-wk normal (n = 10) or HC diet (n = 8), or HC diet supplemented daily with antioxidant vitamins C (1 g) and E (100 IU/kg) (HC + vitamins, n = 7). Renal cortical samples were then scanned three dimensionally with micro-computed tomography, and microvessels were counted in situ. Blood and tissue samples were removed for measurements of superoxide dismutase (SOD) activity, protein expression of the NADP(H)-oxidase subunits gp91phox, p47phox, and p67phox, vascular endothelial growth factor (VEGF) levels and mRNA, VEGF receptors (Flt-1 and Flk-1), the proinflammatory transcription factor NFκB, and the oxidized LDL receptor LOX-1. Microvascular spatial density was significantly elevated in HC compared with normal kidneys but preserved in HC + vitamins. Expression of gp91phox and p67phox was decreased in HC pigs after antioxidant intervention, and SOD improved. The increased renal expression of VEGF and Flk-1 in HC was blunted in HC + vitamins, as were the significant increases in LOX-1, NFκB, and interstitial fibrosis. This study shows that renal cortical neovascularization elicited by diet-induced HC is associated with renal inflammation, fibrosis, and upregulation of VEGF and its receptor Flk-1, likely mediated by increased endogenous oxidative stress. Chronic antioxidant supplementation may preserve the kidney in HC.

AB - Experimental hypercholesterolemia (HC) may lead to microvascular neovascularization, but the underlying pathogenic mechanism remains unclear. We tested the hypothesis that HC-induced intra-renal neovascularization is associated with inflammation and increased oxidative stress, and would be prevented by chronic antioxidant intervention. Kidneys were excised from pigs after a 12-wk normal (n = 10) or HC diet (n = 8), or HC diet supplemented daily with antioxidant vitamins C (1 g) and E (100 IU/kg) (HC + vitamins, n = 7). Renal cortical samples were then scanned three dimensionally with micro-computed tomography, and microvessels were counted in situ. Blood and tissue samples were removed for measurements of superoxide dismutase (SOD) activity, protein expression of the NADP(H)-oxidase subunits gp91phox, p47phox, and p67phox, vascular endothelial growth factor (VEGF) levels and mRNA, VEGF receptors (Flt-1 and Flk-1), the proinflammatory transcription factor NFκB, and the oxidized LDL receptor LOX-1. Microvascular spatial density was significantly elevated in HC compared with normal kidneys but preserved in HC + vitamins. Expression of gp91phox and p67phox was decreased in HC pigs after antioxidant intervention, and SOD improved. The increased renal expression of VEGF and Flk-1 in HC was blunted in HC + vitamins, as were the significant increases in LOX-1, NFκB, and interstitial fibrosis. This study shows that renal cortical neovascularization elicited by diet-induced HC is associated with renal inflammation, fibrosis, and upregulation of VEGF and its receptor Flk-1, likely mediated by increased endogenous oxidative stress. Chronic antioxidant supplementation may preserve the kidney in HC.

UR - http://www.scopus.com/inward/record.url?scp=3042531076&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3042531076&partnerID=8YFLogxK

U2 - 10.1097/01.ASN.0000130428.85603.6B

DO - 10.1097/01.ASN.0000130428.85603.6B

M3 - Article

VL - 15

SP - 1816

EP - 1825

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 7

ER -