The sweetest thing: blocking fructose metabolism to prevent acute kidney injury?

Abstract

Fructose consumption has been linked to hypertension in animal models and human studies, and endogenous fructose metabolism has been shown to promote acute and chronic kidney injury in mice. A recent study published in Nature Communications demonstrates a reduction in ischemic acute kidney injury with genetic knockout or inhibition of fructokinase, which catalyzes the first step in fructose metabolism. Although the role of this pathway in human kidney disease remains unclear, the recent description of several candidate fructokinase inhibitors may allow for clinical studies in the future.

Fructose consumption has been linked to obesity, metabolic syndrome, and hypertension in large epidemiologic studies and small randomized, controlled trials of short-term dietary interventions.^1,2 Because naturally occurring fructose is rarely consumed in the absence of glucose, the effects of fructose are difficult to distinguish from those of other dietary sugars in clinical studies. In animal models in which intake can be more tightly regulated, a high-fructose diet has been shown to cause salt-sensitive hypertension and kidney injury³; however, it remains unclear whether this effect occurs at levels of fructose consumption that are reflective of human diets, even Western diets high in sugar and calories.

Previous studies have demonstrated that the metabolism of endogenously generated fructose also promotes kidney injury in murine models of prerenal acute kidney injury (AKI) and diabetic kidney disease.^4,5 In those studies, kidney injury was significantly reduced in mice with genetic knockout of fructokinase, which catalyzes the first step in fructose utilization despite the absence of dietary fructose intake. Fructose can be generated through the polyol pathway, which converts glucose to sorbitol and fructose (Figure 1), and activation of this pathway in kidney tissue was previously demonstrated in mice subjected to intermittent volume depletion or streptozotocin-induced diabetes.^4,5

Figure 1. Proposed mechanisms of action of luteolin to reduce kidney injury.

The polyol pathway metabolizes excess glucose to sorbitol, and fructose and is upregulated in experimental models of acute kidney injury. Andres-Hernando et al. demonstrated that genetic deletion or inhibition of fructokinase reduces ischemic acute kidney injury in mice. The fructokinase inhibitor luteolin also has other effects that could reduce kidney injury, including the inhibition of topoisomerases, the stabilization of p53, and the inhibition of STAT3.

In the February issue of Nature Communications, Andres-Hernando et al.⁶ report a reduction in ischemic and contrast-induced AKI with genetic knockout of fructokinase in mice. Wild-type and fructokinase knockout mice subjected to bilateral renal artery clamping had evidence of activation of the polyol pathway, as indicated by increased levels of sorbitol, fructose, and the catalytic enzyme aldose reductase in cortical tissue 8 hours after ischemia. After 24 hours, blood urea nitrogen and creatinine and urinary neutrophil gelatinase-associated lipocalin levels were significantly lower in fructokinase-deficient mice compared with wild-type mice. Histology also demonstrated less severe tubular injury in knockout mice. Similar results were observed in a previously described model of contrast-induced nephropathy, with less severe kidney injury in fructokinase knockout mice compared with wild-type mice 24 hours after radiocontrast exposure.⁶

The mechanism whereby fructose metabolism exacerbates AKI is not clear. The authors previously speculated that activation of the polyol pathway and subsequent fructose metabolism promote kidney injury by depleting local adenosine triphosphate (ATP) stores, resulting in the accumulation of uric acid and increased expression of proinflammatory cytokines.^4,5 Although both wild-type and fructokinase knockout mice had increased levels of adenosine diphosphate, uric acid, and proinflammatory cytokines in kidney tissue 8 hours after ischemia, these increases were largely reversed after 24 hours in fructokinase knockout, but not wild-type, mice.⁶ Whether the impact of fructokinase deficiency on ATP levels reflects the actual enzymatic activity of fructokinase or is an indirect consequence of reduced injury remains to be determined. In this regard, there are other important pathways for ATP consumption in AKI as well as decreased ATP formation due to mitochondrial dysfunction. Studies of aldolase inhibitors, which block the next step in fructose metabolism, may be informative.

The results in fructokinase knockout mice largely replicated those of previous studies, suggesting that endogenous fructose generation and metabolism might promote kidney injury in response to a range of experimental insults, including diabetes, volume depletion, ischemia, and radiocontrast. A more novel and potentially important result of the current study is the demonstration that a newly described fructokinase inhibitor, luteolin, also ameliorated AKI when administered before ischemia in wild-type mice. In contrast to many previously studied interventions for AKI, administration of luteolin after ischemia also reduced the severity and duration of kidney injury.⁶ Luteolin was selected from among several recently identified candidate inhibitors, in part because it was previously shown to reduce cisplatin-induced AKI in mice.⁷ The efficacy of luteolin to prevent AKI appeared to be even greater than deletion of fructokinase, raising the possibility that luteolin may have other targets in AKI. Luteolin has other activities that could reduce AKI, including inhibition of topoisomerases, stabilization of p53, and inhibition of STAT3.⁸ Studies examining the effect of luteolin in fructokinase-deficient mice would address this possibility.

The availability of luteolin and other fructokinase inhibitors opens the door for clinical studies to investigate the role of fructose metabolism in human kidney disease, which remains unknown. In a small case-control study (N = 12), the authors demonstrated significantly higher urinary fructose excretion in children undergoing cardiopulmonary bypass in whom AKI developed compared with those in whom it did not develop.⁶ Although these data could suggest activation of the polyol pathway and endogenous fructose generation in response to ischemia, larger and more rigorous studies are needed to confirm the importance of this pathway, as well as the relevance of dietary fructose consumption, in human kidney disease.