1. Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice
- Author
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Javad Habibi, Annayya R. Aroor, Dongqing Chen, Gerald A. Meininger, Francisco I. Ramirez-Perez, Vincent G. DeMarco, Guanghong Jia, James R. Sowers, Zhe Sun, Camila Manrique, Ravi Nistala, Luis A. Martinez-Lemus, Adam Whaley-Connell, and Barron Brady
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Xanthine Oxidase ,Vascular smooth muscle ,Endocrinology, Diabetes and Metabolism ,Allopurinol ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Endocrinology ,Vascular Stiffness ,Internal medicine ,medicine ,Animals ,Xanthine oxidase ,Inflammation ,Kidney ,Proteinuria ,medicine.disease ,Uric Acid ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Diet, Western ,Arterial stiffness ,Uric acid ,medicine.symptom ,Oxidative stress ,medicine.drug - 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 (125 mg/L in drinking water) for 16 weeks. 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.
- Published
- 2017