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Metabolism. 2017 Sep;74:32-40. doi: 10.1016/j.metabol.2017.06.006. Epub 2017 Jun 21.

Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice.

Author information

1
Diabetes and Cardiovascular Research Center, Department of Medicine, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Research Service Harry S Truman Memorial Veterans Hospital, University of Missouri School of Medicine, Columbia, MO 65212, USA. Electronic address: aroora@health.missouri.edu.
2
Diabetes and Cardiovascular Research Center, Department of Medicine, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Research Service Harry S Truman Memorial Veterans Hospital, University of Missouri School of Medicine, Columbia, MO 65212, USA.
3
Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO 65212, USA.
4
Department of Medical Pharmacology and Physiology, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO 65212, USA; Research Service Harry S Truman Memorial Veterans Hospital, University of Missouri School of Medicine, Columbia, MO 65212, USA.
5
Diabetes and Cardiovascular Research Center, Department of Medicine, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Division of Nephrology and Hypertension, Department of Medicine, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Research Service Harry S Truman Memorial Veterans Hospital, University of Missouri School of Medicine, Columbia, MO 65212, USA.
6
Diabetes and Cardiovascular Research Center, Department of Medicine, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Department of Medical Pharmacology and Physiology, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Research Service Harry S Truman Memorial Veterans Hospital, University of Missouri School of Medicine, Columbia, MO 65212, USA.
7
Department of Medical Pharmacology and Physiology, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO 65212, USA.
8
Diabetes and Cardiovascular Research Center, Department of Medicine, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Department of Medical Pharmacology and Physiology, University of Missouri Columbia, School of Medicine, Columbia, MO 65212, USA; Research Service Harry S Truman Memorial Veterans Hospital, University of Missouri School of Medicine, Columbia, MO 65212, USA. Electronic address: sowersj@health.missouri.edu.

Abstract

OBJECTIVE:

Aortic vascular stiffness has been implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) in obese individuals. However, the mechanism promoting these adverse effects are unclear. In this context, promotion of obesity through consumption of a western diet (WD) high in fat and fructose leads to excess circulating uric acid. There is accumulating data implicating elevated uric acid in the promotion of CVD and CKD. Accordingly, we hypothesized that xanthine oxidase(XO) inhibition with allopurinol would prevent a rise in vascular stiffness and proteinuria in a translationally relevant model of WD-induced obesity.

MATERIALS/METHODS:

Four-week-old C57BL6/J male mice were fed a WD with excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L in drinking water) for 16weeks. Aortic endothelial and extracellular matrix/vascular smooth muscle stiffness was evaluated by atomic force microscopy. Aortic XO activity, 3-nitrotyrosine (3-NT) and aortic endothelial sodium channel (EnNaC) expression were evaluated along with aortic expression of inflammatory markers. In the kidney, expression of toll like receptor 4 (TLR4) and fibronectin were assessed along with evaluation of proteinuria.

RESULTS:

XO inhibition significantly attenuated WD-induced increases in plasma uric acid, vascular XO activity and oxidative stress, in concert with reductions in proteinuria. Further, XO inhibition prevented WD-induced increases in aortic EnNaC expression and associated endothelial and subendothelial stiffness. XO inhibition also reduced vascular pro-inflammatory and maladaptive immune responses induced by consumption of a WD. XO inhibition also decreased WD-induced increases in renal TLR4 and fibronectin that associated proteinuria.

CONCLUSIONS:

Consumption of a WD leads to elevations in plasma uric acid, increased vascular XO activity, oxidative stress, vascular stiffness, and proteinuria all of which are attenuated with allopurinol administration.

KEYWORDS:

Arterial stiffness; Macrophage polarization; Obesity; Proteinuria; Uric acid

PMID:
28764846
PMCID:
PMC5577816
DOI:
10.1016/j.metabol.2017.06.006
[Indexed for MEDLINE]
Free PMC Article

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