Mechanisms by Which Dehydration May Lead to Chronic Kidney Disease

TLDR

Fructose consumption is linked to metabolic syndrome, diabetes, cardiovascular disease, and chronic kidney disease, and within cells it is phosphorylated by ketohexokinase, depleting ATP, generating AMP, and producing uric acid via xanthine oxidoreductase. The study aimed to determine whether fructose directly induces inflammatory responses in human kidney proximal tubular cells and whether these effects are mediated through ketohexokinase. The authors confirmed xanthine oxidoreductase expression and activity in HK‑2 cells by detecting its mRNA and measuring uric acid production by mass spectrometry. Fructose at post‑prandial concentrations stimulated MCP‑1 secretion and reactive oxygen species in HK‑2 cells in a ketohexokinase‑dependent manner, and both uric acid accumulation and inhibition of NADPH oxidase or xanthine oxidoreductase blocked this response, indicating that fructose triggers redox‑ and urate‑dependent inflammation in proximal tubular cells.

Abstract

Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox- and urate-dependent inflammatory mediators in proximal tubular cells.