Ketohexokinase, the principal fructose-metabolising enzyme is downregulated in the kidneys of rodents and humans with chronic kidney disease
Year: 2026
Type: article
Abstract: Background and hypothesis Excessive renal exposure to fructose, either via oral consumption or de novo production via the polyol pathway is associated with kidney injury. This detrimental effect is attributed to the rate limiting enzyme in the ‘fructolytic’ pathway, ketohexokinase-C, activity of which results in intracellular phosphate depletion, uric acid production and inflammation. Multiple factors which characterise chronic kidney disease including hypoxia and uric acid production upregulate ketohexokinase-C, yet the expression profile of this enzyme in CKD has not been characterised. If upregulated in the context of chronic kidney disease ketohexokinase-C presents an attractive therapeutic target to slow disease progression. Hypothesis Renal ketohexokinase-C is upregulated in the context of chronic kidney disease. Methods Chronic kidney disease was induced using an adenine diet model and validated by measuring creatinine clearance, urine protein creatinine ratio, Kidney Injury Molecule-1 and via histology. Ketohexokinase and megalin were quantified by Western blotting analysis. RT-qPCR was used to quantify KHK-C and KHK-A mRNA. RNA-Sequencing data of 24 human kidney biopsy samples (GSE137570) were identified for in silico validation, patient eGFR and percent tubular atrophy and interstitial fibrosis being matched to each sample. Results Unexpectedly, ketohexokinase protein and mRNA were significantly decreased in adenine treated animals compared with controls (N = 6, p=0.0001) and (N = 4, p=0.0002). This finding was replicated in a second cohort of animals. Furthermore, a significant positive linear association was observed between creatinine clearance and ketohexokinase protein in Wistar rats (N = 8, p<0.0001). The same association was evident in silico between eGFR and KHK RNA adjusted for interstitial fibrosis in human kidney (N = 24 p=<0.0001). Conclusion Contrary to our hypothesis, these findings demonstrate reduction in protein and mRNA expression of the principal fructose metabolising enzyme in chronic kidney disease. This is at odds with existing data linking fructose metabolism with acute kidney injury and may represent a compensatory response limiting associated ATP depletion and inflammation in the chronic setting.
Source: Frontiers in Nephrology
Institutions: University College London, The Royal Free Hospital
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,353
OpenAlex ID: W7225831372