Fructose in the kidney: from physiology to pathology

Abstract

The Warburg effect is a unique property of cancer cells, in which glycolysis is activated instead of mitochondrial respiration despite oxygen availability. However, recent studies found that the Warburg effect also mediates non-cancer disorders, including kidney disease. Currently, diabetes or glucose has been postulated to mediate the Warburg effect in the kidney, but it is of importance that the Warburg effect can be induced under nondiabetic conditions. Fructose is endogenously produced in several organs, including the kidney, under both physiological and pathological conditions. In the kidney, fructose is predominantly metabolized in the proximal tubules; under normal physiologic conditions, fructose is utilized as a substrate for gluconeogenesis and contributes to maintain systemic glucose concentration under starvation conditions. However, when present in excess, fructose likely becomes deleterious, possibly due in part to excessive uric acid, which is a by-product of fructose metabolism. A potential mechanism is that uric acid suppresses aconitase in the Krebs cycle and therefore reduces mitochondrial oxidation. Consequently, fructose favors glycolysis over mitochondrial respiration, a process that is similar to the Warburg effect in cancer cells. Activation of glycolysis also links to several side pathways, including the pentose phosphate pathway, hexosamine pathway, and lipid synthesis, to provide biosynthetic precursors as fuel for renal inflammation and fibrosis. We now hypothesize that fructose could be the mediator for the Warburg effect in the kidney and a potential mechanism for chronic kidney disease.

Keywords: Fructose; Glycolysis; Inflammation; Mitochondria; Proximal tubules; Uric acid; Warburg effect.

Figure 1.. Current concepts regarding the metabolic pathways of dietary fructose.

Dietary fructose is absorbed by enterocytes via glucose transporter (GLUT) 5 at the apical membrane of enterocytes and is likely utilized as a substrate for gluconeogenesis. Interestingly, intestinal fructose metabolism determines an individual’s preference for sweet tastes and sugar intake but does not contribute to the development of the metabolic syndrome. When present in excess, fructose may saturate intestinal metabolic capacity and spill over to the colon where fructose can be digested by gut microbiota and utilized for the generation of tricarboxylic acid (TCA) intermediates, essential amino acids (AA), and short-chain fatty acids (SCFA). Alternatively, fructose exceeding the metabolic capacity of enterocytes is excreted from GLUT2 at the basal membrane and passes into the portal circulation, and reaches the hepatocytes. The fructose is then reabsorbed via GLUT2 at the surface of hepatocyte to be metabolized, likely driving the metabolic syndrome. Hepatic fructose metabolism is associated with increased hepatic fatty acid synthesis and malonyl-CoA levels, and a reduction in fatty acid oxidation. Similar to the enterocyte, excessive fructose likely escapes from hepatocyte into the systemic circulation. The kidney also plays a role in reabsorption and excretion of fructose. At physiological concentrations, fructose is utilized for gluconeogenesis, whereas it causes kidney injury when present in excess.

Figure 2.. Fructose transporters and metabolism in the proximal tubules.

In the proximal tubules, urinary fructose is reabsorbed at the apical membrane of the epithelial cells via several types of fructose transporters. The glucose transporter (GLUT) 5 is considered to be a major transporter for fructose. The sodium glucose cotransporter 5 (SGLT5) is a high-affinity kidney-specific transporter for fructose and mannose in humans and mice, while the rat sodium-dependent glucose transporter-1 (rNaGLT1) is also expressed in both convoluted and straight proximal tubules in the rat and also mediates fructose transport. Under physiological conditions or during starvation, fructose is utilized as a substrate for gluconeogenesis. In turn, during satiation or when fructose is in excess, fructose is metabolized in the cytosol to produce several fructose metabolites, including uric acid. The GLUT2 facilitative transporter is expressed in the basal membrane. When fructose concentrations are higher in the cytosol than in the blood of peritubular capillary, GLUT2 transports intracellular fructose into the blood in the peritubular capillary. Likewise, GLUT9a, another facilitative transporter, is expressed in the basolateral membrane and favors urate transport back into the circulation from the tubular cells.

Figure 3.. Postulate mechanism of fructose-induced kidney disease.

Fructose, arising either from the diet or from endogenous production under pathological conditions, acts on the tubular epithelial cells, endothelial cells, and macrophages through fructose transporters, such as glucose transporter 5 (GLUT5), to cause inflammation and fibrosis in the kidney. AR, aldose reductase; eNOS, endothelial NO synthase; ICAM-1, intercellular adhesion molecule-1.

Figure 4.. Several pathways downstream from fructose metabolism.

Fructose is initially metabolized to fructose 1-phosphate by fructokinase, which rapidly sequesters phosphate, consequently activating adenosine monophosphate (AMP) deaminase to cleave AMP to inosine monophosphate (IMP). Sequential enzymatic activation metabolizes IMP and eventually produces uric acid. Uric acid subsequently inhibits aconitase in the tricarboxylic acid (TCA) cycle to suppress mitochondrial respiration. Glycolysis is preferentially activated, and several metabolites are fed into several side pathways, including the pentose phosphate pathway (PPP) and hexosamine pathway (HXP), which aberrantly activate energy production, synthesis of biosynthetic precursors, and redox homeostasis. ADP, adenosine diphosphate; AldoB, aldorase B; ATP, adenosine triphosphate; DHAP, dihydroxyacetone phosphate; E4P, erythrose 4-phosphate; F1,6P, fructose 1,6-biphosphate; FK, fructokinase; Fru1P, fructose 1-phosphate; Fru6P, fructose 6-phosphate; G3P, glyceraldehyde 3-phosphate; GA, glyceraraldehyde; Glc6P, glucose 6-phosphate; GSH, glutathione; GSSH, glutathione-S-S-glutathione; NADP+, nicotinamide adenine dinucleotide phosphate; NonOx, non-oxidative; Ox, oxidative; R5P, ribose 5-phosphate; Ru5P, ribulose 5-phosphate; S7P, sedoheptulose 7-phosphate; TKT, transketolase; X5P, xylulose 5-phosphate; 6PG, 6-phosphogluconate.

Figure 5.. Current hypothesis of the pathophysiology of fructose in the kidney.

In addition to dietary fructose, fructose can be produced endogenously as a result of several pathological conditions in the kidney. During starvation, fructose is utilized for gluconeogenesis in the proximal tubular cells and excreted into the systemic circulation to maintain serum glucose concentrations. In turn, when in excess or during satiation, fructose is associated with aberrant energy production, biomass synthesis, and redox balance with uric acid production, resulting in the Warburg effect in the kidney. Together with such reactions, fructose also causes endothelial NO synthase (eNOS) uncoupling in endothelial cells and release inflammatory cytokines. Fructose also stimulates the Na/H exchanger to accelerate sodium absorption, leading to salt-sensitive hypertension (HT). ICAM-1, intercellular adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1, mOXPHOS, mitochondrial oxidative phosphorylation; Osm, osmolarity.