ISOFORM-SPECIFIC ROLE OF FRUCTOKINASE-C IN DIABETIC KIDNEY DISEASE

In hyperglycemia, glucose is converted to endogenous fructose via the polyol pathway, which is further metabolized by fructokinase, also known as ketohexokinase (KHK). KHK exists as two alternatively spliced isoforms of the KHK gene, KHK-A and KHK-C, with distinct tissue distributions and enzymatic activities. Our prior studies demonstrated that excessive fructose metabolism accelerates both metabolic syndrome and diabetic kidney disease (DKD), while global loss of KHK prevents these pathologies. Interestingly, deletion of KHK-A alone aggravates renal damage, implying a possible protective effect of KHK-A when KHK-C is active. However, the precise contribution of KHK-C to DKD pathogenesis remains to be elucidated.

Three genetically modified mice, KHK-A knockout (KO), KHK-A/C double KO, and KHK-C KO were used. Diabetes was induced by multiple low-dose streptozotocin intraperitoneal injections. We evaluated renal function, urinary albumin excretion, tubular injury markers, histopathological alterations, and inflammatory gene expression. Unbiased metabolomic analysis was also performed.

Whereas KHK-A KO mice exhibited severe albuminuria and increased NGAL excretion, KHK-C KO mice showed significant attenuation of these parameters. Renal mRNA levels of CCL2 and F4/80 were lower in KHK-C KO mice compared with WT and KHK-A KO, consistent with reduced inflammation. The phenotype of KHK-A/C KO mice resembled that of KHK-C KO mice, indicating that KHK-C is primarily responsible for the pathogenic effects of fructose metabolism.

These findings demonstrate that KHK-C–driven fructose metabolism promotes DKD progression, while KHK-A may exert a counterbalancing, protective effect. Selective inhibition of KHK-C effectively suppresses harmful fructose metabolism and mitigates renal injury in DKD, highlighting KHK-C as a promising therapeutic target.