Kidney Week

Abstract: SA-PO0873

Fructokinase-C Promotes Metabolic Syndrome and Diabetic Kidney Disease

Session Information

• Health Maintenance, Nutrition, and Metabolism
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Health Maintenance, Nutrition, and Metabolism

• 1500 Health Maintenance, Nutrition, and Metabolism

Authors

• Ishimoto, Takuji, Aichi Ika Daigaku, Nagakute, Aichi Prefecture, Japan

Takuji Ishimoto, MD, PhD

• Tsuboi, Toshiki, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi Prefecture, Japan

Toshiki Tsuboi, MD

• Imai, Kentaro, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi Prefecture, Japan

Kentaro Imai

• Yamaguchi, Makoto, Aichi Ika Daigaku, Nagakute, Aichi Prefecture, Japan

Makoto Yamaguchi, MD, PhD

• Kinashi, Hiroshi, Aichi Ika Daigaku, Nagakute, Aichi Prefecture, Japan

Hiroshi Kinashi, MD, PhD

• Furuhashi, Kazuhiro, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi Prefecture, Japan

Kazuhiro Furuhashi, MD, PhD

• Ito, Yasuhiko, Aichi Ika Daigaku, Nagakute, Aichi Prefecture, Japan

Yasuhiko Ito, MD, PhD

• Maruyama, Shoichi, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi Prefecture, Japan

Shoichi Maruyama, MD, PhD

Background

Enhanced endogenous fructose production through the polyol pathway contributes to metabolic and renal injury via fructokinase/ketohexokinase (KHK)-mediated metabolism. KHK consists of two isoforms, KHK-A and KHK-C. We previously demonstrated that global deletion of both isoforms ameliorates metabolic syndrome and diabetic kidney disease (DKD), whereas deletion of KHK-A alone worsens renal injury. However, the role of KHK-C remains unclear.

Methods

We newly generated KHK-C knockout (KO) mice using CRISPR–Cas9 genome editing. For DKD experiments, wild-type (WT), KHK-A KO, KHK-A/C double KO, and KHK-C KO mice were rendered diabetic by low-dose streptozotocin injections. For metabolic syndrome experiments, WT, KHK-A/C double KO, and KHK-C KO mice were exposed to fructose water loading. Renal injury, metabolic parameters, inflammatory and fibrotic markers, and metabolomic profiles were evaluated.

Results

In the DKD model, KHK-C KO mice exhibited attenuated albuminuria, tubular injury, and renal inflammatory/fibrotic markers compared with WT and KHK-A KO mice. Metabolomic analysis showed suppression of fructose metabolism in KHK-C KO kidneys, including reduced fructose-1-phosphate accumulation, higher ATP/ADP and NAD(P)(H) levels, and lower β-hydroxybutyrate and serum lactate levels.
In the fructose-induced metabolic syndrome model, KHK-C KO mice showed marked protection against body weight gain and metabolic abnormalities, closely resembling KHK-A/C double KO mice. In contrast to our previous findings that KHK-A KO exacerbated metabolic syndrome, selective deletion of KHK-C suppressed disease progression.

Conclusion

KHK-C plays a key pathogenic role in metabolic syndrome and DKD. Selective inhibition of KHK-C reproduced the protective phenotype observed in KHK-A/C double KO mice while preserving KHK-A activity, suggesting KHK-C as a promising therapeutic target.