Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

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.

Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice

“…Foods with added sugars are not necessarily sweeter, but this sweetness is a powerful aversion to those with HFI (49). In addition, it has become increasingly apparent that fructose can be produced endogenously in the body by the activation of aldose reductase and the polyol pathway (50,51). These reports demonstrate that endogenous fructose production and its metabolism through Khk are important del-jci.org Volume 128 Number 6 June 2018…”

“…Khk activity was determined as previously described with slight modifications (50). Briefly, liver samples were first homogenized in 20 mM Tris-HCl, pH 7.5, 150 mM KCl, 1 mM EDTA, and 1 mM DTT using a polytron homogenizer, and centrifuged for 10 minutes at 13,000 rpm at 4°C.…”

Fructose metabolism and metabolic disease

“…This may be a mechanism by which severe hyperglycemia may exacerbate cardiometabolic risks. Additionally, Lanaspa et al report that endogenous fructose production and KHK activation within the kidney contribute to the development of diabetic nephropathy (112). Although sorbitol dehydrogenase is expressed at high levels in human liver (113), whether this pathway is sufficiently active in humans to play an adverse metabolic role will require further investigation.…”

Adiponectin Resistance and Proinflammatory Changes in the Visceral Adipose Tissue Induced by Fructose Consumption via Ketohexokinase-Dependent Pathway

“…Insufficient blocking of ACC in the kidney, one of the major sites of KHK-C expression (see Introduction), could potentially create conditions for ectopic lipogenesis in a KHK-dependent fashion, which was not yet addressed in experiments. However, fructose-induced KHK-dependent injury in the kidney (37) and in the KHK-expressing proximal tubular cells (12) is well documented.…”