Endogenous Fructose Metabolism Could Explain the Warburg Effect and the Protection of SGLT2 Inhibitors in Chronic Kidney Disease.

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.
Competing Interests: ML, LS-L and RJ have equity in a start-up company developing fructokinase inhibitors (Colorado Research Partners LLC). TN and RJ also have equity with XORTX therapeutics which is developing novel xanthine oxidase inhibitors. RJ is also a consultant for Horizon Pharmaceuticals, Inc. BR-I is a recipient of the Cátedra Salvador Zubirán, Universidad Nacional de México and Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán, Ciudad de México, Mexico. PB has acted as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli-Lilly, Sanofi, Novo Nordisk, and Horizon Pharma. PB serves on the advisory boards of AstraZeneca, Boehringer Ingelheim, Novo Nordisk and XORTX. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Nakagawa, Sanchez-Lozada, Andres-Hernando, Kojima, Kasahara, Rodriguez-Iturbe, Bjornstad, Lanaspa and Johnson.)