| Abstract: | Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase–deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.Diabetic nephropathy is the most common kidney disease causing ESRD worldwide and also one of the most difficult diseases to treat. To date, treatment includes tight blood glucose and BP control and inhibition of the renin-angiotensin-aldosterone system. These efforts typically slow but do not arrest the progression of kidney disease.1 It is therefore imperative to better understand the mechanisms responsible for renal injury and to develop additional therapies.Recently, fructose has emerged as a potential nephrotoxin. Fructose-fed rats develop modest tubulointerstitial injury,2 and fructose supplementation accelerates renal disease in the remnant kidney model.3 While all studies to date have focused on dietary fructose as the source of fructose, fructose can also be generated from glucose in diabetes because of the activation of the polyol pathway in the proximal tubule. To date, no studies have examined the role of this endogenous fructose production or fructoneogenesis in driving diabetic nephropathy. Therefore, we tested the hypothesis that mice lacking fructokinase-ketohexokinase (khk−/−) show protection from diabetic nephropathy, even in the absence of dietary fructose, as a result of their inability to metabolize endogenously produced fructose. |
