Fructose and uric acid in diabetic nephropathy

Abstract

Clinical studies have reported associations between serum uric acid levels and the development of diabetic nephropathy, but the underlying mechanisms remain elusive. There is evidence from animal studies that blocking uric acid production protects the kidney from tubulointerstitial injury, which may suggest a causal role for uric acid in the development of diabetic tubular injury. In turn, when fructose, which is endogenously produced in diabetes via the polyol pathway, is metabolised, uric acid is generated from a side-chain reaction driven by ATP depletion and purine nucleotide turnover. For this reason, uric acid derived from endogenous fructose could cause tubulointerstitial injury in diabetes. Accordingly, our research group recently demonstrated that blocking fructose metabolism in a diabetic mouse model mitigated the development of tubulointerstitial injury by lowering tubular uric acid production. In this review we discuss the relationship between uric acid and fructose as a novel mechanism for the development of diabetic tubular injury.

Figures

Fig. 1

A proposed mechanism by which a high concentration of urinary glucose my stimulate urate excretion. Glu, glucose; SGLT, sodium-dependent glucose transporter; UA, uric acid

Fig. 2

From polyol pathway to uric acid production. F1P, fructose-1-phosphate; Fr, fructose; Glu, glucose; IMP, inosine monophosphate; Sor, sorbitol

Fig. 3

A proposed mechanism for tubular injury in diabetes. F1P, fructose-1-phosphate; FK, fructokinase; Fr, fructose; Glu, glucose; UA, uric acid; XO, xanthine oxidase

Fig. 4

Fructose impairs renal tubular epithelial cells and endothelial cells. Fr, fructose; Gl5, GLUT5