Fructose Production and Metabolism in the Kidney

Abstract

Understanding fructose metabolism might provide insights to renal pathophysiology. To support systemic glucose concentration, the proximal tubular cells reabsorb fructose as a substrate for gluconeogenesis. However, in instances when fructose intake is excessive, fructose metabolism is costly, resulting in energy depletion, uric acid generation, inflammation, and fibrosis in the kidney. A recent scientific advance is the discovery that fructose can be endogenously produced from glucose under pathologic conditions, not only in kidney diseases, but also in diabetes, in cardiac hypertrophy, and with dehydration. Why humans have such a deleterious mechanism to produce fructose is unknown, but it may relate to an evolutionary benefit in the past. In this article, we aim to illuminate the roles of fructose as it relates to gluconeogenesis and fructoneogenesis in the kidney.

Keywords: fructolysis; fructoneogenesis; fructose; gluconeogenesis; glycolysis.

Figure 1.

The S1 and S2 of the proximal tubular cells cooporately metabolize fructose. Both proximal convoluted tubules (PCT) and proximal straight tubules (PST) participate in fructose (Fru) metabolism. AldoB, aldolase B; DHAP, dihydroxyacetate phosphate; FBPase, fructose 1,6-bisphosphatase; FK, fructokinase; Fru1P, fructose 1-phosphate; Fru1,6P₂, fructose 1,6 bisphosphate; Glc, glucose; Glc6P, glucose 6-phosphate; G3P; glyeraldehyde 3-phosphate; G6Pase, glucose 6-phosphatase; Glut2/5, glucose transporter 2/5.

Figure 2.

Both fructolysis and fructogenesis occuring in the kidney are modulated by uric acid. AR, aldose reductase; FA, fatty acid; FK, fructokinase; Fru, fructose; Fru6P, fructose 6-phosphate; Fru1,6P₂, fructose 1,6 bisphosphate; DHAP, dihydroxyacetate phosphate; Glc, glucose; Glc6P, glucose 6-phosphate; G3P; glyeraldehyde 3-phosphate; OXPHOS, mitochondrial oxidative phosphorylation; PEP, phosphoenolpyruvate; PPP, pentose phosphate pathway; SDH, sorbitol dehydrogenase; TCA, tricarboxylic acid cycle.

Figure 3.

Both dietary and endogenously produced fructose cause CKD, nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. FK, fructokinase; NO, nitric oxide.