P0964EFFECTS OF XANTHINE OXIDASE INHIBITORS AND DAPAGLIFLOZIN ON RENAL GLUCOSE AND URATE TRANSPORTERS IN METABOLIC SYNDROME
Authors: Ng Hwee-Yeong , Lee Chien-Te , Leung Foong-Fah , Lee Yuai-Ting 
Published: June 2020

Abstract

Background and Aims
Metabolic syndrome consists of several medical conditions that collectively predict the risk for cardiovascular disease. Hyperglycemia and hyperuricemia are the major disorders of metabolic syndrome. Kidney reabsorbs almost all filtrated glucose by active transport at normal concentrations of plasma glucose via members of the sodium glucose transport (SGLT) family. Besides, the kidney plays a pivotal role in handling uric acid homeostasis. Uric acid is mainly controlled by urate transporter (UAT), urate anion exchanger 1 (URAT1) and glucose transporter 9 (GLUT9). The aims of the study were to determine the alteration of renal glucose and uric acid transporters in animals with metabolic syndrome after treatment of xanthine oxidase inhibitors and SGLT2 inhibitor.

Method
Sprague-Dawley rats were fed with normal chow (Control) or high fructose diet (60%) for totally 6 months. For those animals fed with high fructose diet for 3 months, they were divided into 4 groups including high fructose diet without treatment (FR), treatment with allopurinol (150 mg/L in drinking water), with febuxostat (30 mg/L in drinking water) or with dapagliflozin (1mg/kg/day intraperitoneal injection). Blood, urine and blood pressure were collected and measured at the end of study. Gene and protein expression of renal glucose and uric acid transporters were determined by reverse transcriptase polymerase chain reaction. The changes of transporters were then confirmed by immunohistochemical staining.

Results
High-fructose diet induced higher levels of fasting glucose, insulin resistance index, uric acid, triglyceride and blood pressure in FR group (all p &lt;0.05 vs. control). Treatment of allopurinol, febuxostat and dapagliflozin reduced body weight significantly. Fasting glucose, insulin resistance index and hyperuricemia were improved in all drug treatment groups (all p &lt;0.05). In the kidney, high fructose diet significantly upregulated SGLT1, SGLT2 and GLUT2 but downregulated GLUT1 expression. Urate transporters, including GLUT9, UAT and URAT1 were also increased (p &lt;0.05). The improvement of insulin resistance by xanthine oxidase inhibitors was associated with suppression of renal SGLT1, SGLT2 and GLUT2 expression. Dapagliflozin alleviated hyperuricemia and induced uricosuria without affecting serum xanthine oxidase activity. Compared to FR, dapagliflozin significantly inhibited fructose-induced overexpression of GLUT9, UAT and URAT1 in the kidney.

Conclusion
Long term high fructose diet induced metabolic syndrome in rats. Treatment of xanthine oxidase inhibitors and dapagliflozin ameliorated components of metabolic syndrome. Both allopurinol and febuxostat improved insulin resistance in association with suppression of renal SGLT1, SGLT2 and GLUT2 expression. Although dapagliflozin and xanthine oxidase inhibitors reduced uric acid in different mechanisms, they shared a similar molecular changes in the kidney by downregulating GLUT9, UAT and URAT1 expression.