Tomohito Doke1, Takuji Ishimoto2, Takahiro Hayasaki3, Satsuki Ikeda4, Masako Hasebe4, Akiyoshi Hirayama4, Tomoyoshi Soga4, Noritoshi Kato3, Tomoki Kosugi3, Naotake Tsuboi3, Miguel A Lanaspa5, Richard J Johnson5, Kenji Kadomatsu6, Shoichi Maruyama3. 1. Departments of Nephrology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Departments of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. 2. Departments of Nephrology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: i-takuji@med.nagoya-u.ac.jp. 3. Departments of Nephrology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. 4. Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan. 5. Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO 80045, USA. 6. Departments of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Abstract
OBJECTIVE: Ketohexokinase (KHK), a primary enzyme in fructose metabolism, has two isoforms, namely, KHK-A and KHK-C. Previously, we reported that renal injury was reduced in streptozotocin-induced diabetic mice which lacked both isoforms. Although both isoforms express in kidney, it has not been elucidated whether each isoform plays distinct roles in the development of diabetic kidney disease (DKD). The aim of the study is to elucidate the role of KHK-A for DKD progression. MATERIALS AND METHODS: Diabetes was induced by five consecutive daily intraperitoneal injections of streptozotocin (50 mg/kg) in C57BL/6J wild-type mice, mice lacking KHK-A alone (KHK-A KO), and mice lacking both KHK-A and KHK-C (KHK-A/C KO). At 35 weeks, renal injury, inflammation, hypoxia, and oxidative stress were examined. Metabolomic analysis including polyol pathway, fructose metabolism, glycolysis, TCA (tricarboxylic acid) cycle, and NAD (nicotinamide adenine dinucleotide) metabolism in kidney and urine was done. RESULTS: Diabetic KHK-A KO mice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, dihydroxyacetone phosphate (DHAP), TCA cycle intermediate levels, and severe inflammation. In contrast, renal injury was prevented in diabetic KHK-A/C KO mice compared to both wild-type and KHK-A KO diabetic mice. Further, diabetic KHK-A KO mice contained decreased renal NAD+ level with the increase of renal hypoxia-inducible factor 1-alpha expression despite having increased renal nicotinamide (NAM) level. CONCLUSION: These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD.
OBJECTIVE:Ketohexokinase (KHK), a primary enzyme in fructose metabolism, has two isoforms, namely, KHK-A and KHK-C. Previously, we reported that renal injury was reduced in streptozotocin-induced diabeticmice which lacked both isoforms. Although both isoforms express in kidney, it has not been elucidated whether each isoform plays distinct roles in the development of diabetic kidney disease (DKD). The aim of the study is to elucidate the role of KHK-A for DKD progression. MATERIALS AND METHODS:Diabetes was induced by five consecutive daily intraperitoneal injections of streptozotocin (50 mg/kg) in C57BL/6J wild-type mice, mice lacking KHK-A alone (KHK-A KO), and mice lacking both KHK-A and KHK-C (KHK-A/C KO). At 35 weeks, renal injury, inflammation, hypoxia, and oxidative stress were examined. Metabolomic analysis including polyol pathway, fructose metabolism, glycolysis, TCA (tricarboxylic acid) cycle, and NAD (nicotinamide adenine dinucleotide) metabolism in kidney and urine was done. RESULTS:Diabetic KHK-A KOmice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, dihydroxyacetone phosphate (DHAP), TCA cycle intermediate levels, and severe inflammation. In contrast, renal injury was prevented in diabetic KHK-A/C KO mice compared to both wild-type and KHK-A KO diabeticmice. Further, diabetic KHK-A KOmice contained decreased renal NAD+ level with the increase of renal hypoxia-inducible factor 1-alpha expression despite having increased renal nicotinamide (NAM) level. CONCLUSION: These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD.
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