Abstract
Chronic low-grade inflammation underlies the pathogenesis of non-communicable diseases, including chronic kidney diseases (CKD). Inflammation is a biologically active process accompanied with biochemical changes involving energy, amino acid, lipid and nucleotides. Recently, glycolysis has been observed to be increased in several inflammatory disorders, including several types of kidney disease. However, the factors initiating glycolysis remains unclear. Added sugars containing fructose are present in nearly 70 percent of processed foods and have been implicated in the etiology of many non-communicable diseases. In the kidney, fructose is transported into the proximal tubules via several transporters to mediate pathophysiological processes. Fructose can be generated in the kidney during glucose reabsorption (such as in diabetes) as well as from intra-renal hypoxia that occurs in CKD. Fructose metabolism also provides biosynthetic precursors for inflammation by switching the intracellular metabolic profile from mitochondrial oxidative phosphorylation to glycolysis despite the availability of oxygen, which is similar to the Warburg effect in cancer. Importantly, uric acid, a byproduct of fructose metabolism, likely plays a key role in favoring glycolysis by stimulating inflammation and suppressing aconitase in the tricarboxylic acid cycle. A consequent accumulation of glycolytic intermediates connects to the production of biosynthetic precursors, proteins, lipids, and nucleic acids, to meet the increased energy demand for the local inflammation. Here, we discuss the possibility of fructose and uric acid may mediate a metabolic switch toward glycolysis in CKD. We also suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors may slow the progression of CKD by reducing intrarenal glucose, and subsequently fructose levels.
Highlights
Chronic kidney disease (CKD) has increased in the last decades and is a major cause of morbidity and mortality
Glycolysis is the metabolic pathway that converts glucose into pyruvate, that can enter the tricarboxylic acid (TCA) cycle in mitochondria where adenosine triphosphate (ATP) is generated through oxidative phosphorylation
We have previously suggested that the blocking of glucose uptake into the S1 and S2 segments of the proximal tubule might increase the amount of glucose reabsorbed by the S3 segment, which could lead to sufficient fructose generation that its metabolism by fructokinase could result in tubular injury and acute kidney injury [63]
Summary
Chronic kidney disease (CKD) has increased in the last decades and is a major cause of morbidity and mortality. We present a novel hypothesis that fructose, either provided in the diet or produced endogenously, could play a key role in causing disease through its ability to induce inflammation through a Warburg effect. Research has implicated a role for fructose in many noncommunicable diseases, including obesity, diabetes, nonalcoholic fatty liver disease, and heart disease [12, 13] and both acute and chronic kidney disease [5, 6, 14, 15] This has been ascribed to fructose’s effect to stimulate oxidative stress, endothelial dysfunction, stimulation of vasopressin, and uric acid generation [12, 13, 16]. We suggest that the Warburg effect due to fructose might have a role in chronic kidney disease (CKD)
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