Insulin stimulates uric acid reabsorption via regulating urate transporter 1 and ATP-binding cassette subfamily G member 2

• Published in: American journal of physiology. Renal physiology 2017-09, Vol.313 (3), p.F826-F834
• Main Authors: Toyoki, Daigo, Shibata, Shigeru, Kuribayashi-Okuma, Emiko, Xu, Ning, Ishizawa, Kenichi, Hosoyamada, Makoto, Uchida, Shunya
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Animals; Anion Transport Proteins - metabolism; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - metabolism; Binding sites; Blood glucose; Blood Glucose - drug effects; Blood Glucose - metabolism; Cell Line; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Type 1 - chemically induced; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - physiopathology; Epithelial cells; Excretion; Glucosides - pharmacology; Hyperinsulinemia; Hyperuricemia; Hypoglycemic agents; Hypoglycemic Agents - pharmacology; Insulin; Insulin - pharmacology; Kidney Tubules - drug effects; Kidney Tubules - metabolism; Kidney Tubules - physiopathology; Kidneys; Male; Na+/glucose cotransporter; Proteins; Rats, Sprague-Dawley; Reabsorption; Renal Elimination - drug effects; Renal function; Renal Reabsorption - drug effects; Sodium; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Sodium-Glucose Transporter 2 - metabolism; Streptozocin; Thiophenes - pharmacology; Time Factors; Uric acid; Uric Acid - metabolism; Uric Acid - urine
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00012.2017

Accumulating data indicate that renal uric acid (UA) handling is altered in diabetes and by hypoglycemic agents. In addition, hyperinsulinemia is associated with hyperuricemia and hypouricosuria. However, the underlying mechanisms remain unclear. In this study, we aimed to investigate how diabetes and hypoglycemic agents alter the levels of renal urate transporters. In insulin-depleted diabetic rats with streptozotocin treatment, both UA excretion and fractional excretion of UA were increased, suggesting that tubular handling of UA is altered in this model. In the membrane fraction of the kidney, the expression of urate transporter 1 (URAT1) was significantly decreased, whereas that of ATP-binding cassette subfamily G member 2 (ABCG2) was increased, consistent with the increased renal UA clearance. Administration of insulin to the diabetic rats decreased UA excretion and alleviated UA transporter-level changes, while sodium glucose cotransporter 2 inhibitor (SGLT2i) ipragliflozin did not change renal UA handling in this model. To confirm the contribution of insulin in the regulation of urate transporters, normal rats received insulin and separately, ipragliflozin. Insulin significantly increased URAT1 and decreased ABCG2 levels, resulting in increased UA reabsorption. In contrast, the SGLT2i did not alter URAT1 or ABCG2 levels, although blood glucose levels were similarly reduced. Furthermore, we found that insulin significantly increased endogenous URAT1 levels in the membrane fraction of NRK-52E cells, the kidney epithelial cell line, demonstrating the direct effects of insulin on renal UA transport mechanisms. These results suggest a previously unrecognized mechanism for the anti-uricosuric effects of insulin and provide novel insights into the renal UA handling in the diabetic state.