Abstract P199: Uric Acid Promotes Vascular Stiffness, Immune Inflammatory Response and Proteinuria in Western Diet Fed Mice

Abstract

Increased consumption of a diet high in fructose and fat (western diet, WD) is associated with an increase in cardiovascular disease (CVD) and kidney injury. In this regard, excess hepatic production of uric acid generated from excess fructose consumption is emerging as a risk factor for vascular stiffness, which underpins CVD and kidney injury. We hypothesized that a WD would increase uric acid levels and cardiovascular and renal xanthine oxidase (XO) activity and associated increased vascular stiffness and proteinuria. Furthermore, we proposed that inhibition of XO activity would prevent arterial stiffening and reduce proteinuria in a clinically relevant model of WD-induced CVD and renal injury. Four week-old C57BL6/J male mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) with or without allopurinol (125mg/L), a potent XO inhibitor for 16 weeks. XO inhibition significantly attenuated WD-induced increases in plasma and urine uric acid levels and aortic XO activity (WD, 0.225 + 0.031 mU/mL WD + allopurinol, 0.097+ 0.026mU/mL, P<0.05), as well as proteinuria (WD, 20.92 + 2.66 mg/ mg creatinine, WD + allopurinol, 13.48 + 1.56 mg/mg creatinine, P<0.05). XO inhibition had no effect on increases in body weight, fat mass, and HOMA-IR promoted by the WD. Blood pressure was not different between any of the groups. Stiffness of aortic endothelial cells, extracellular matrix and vascular smooth muscle cells, as determined by atomic force microscopy, was significantly increased in WD mice and this was prevented by XO inhibition. WD induced a significant macrophage pro-inflammatory response in aorta that was significantly suppressed by XO inhibition. Collectively, these findings support the notion that increased XO activity in the vasculature and kidney and increased hepatic production of uric acid secondary to consumption of a WD promotes vascular stiffness, vascular inflammation and a maladaptive immune response that lead to vascular stiffness and kidney injury.