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Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice.

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.

SUBMITTER: Doke T

PROVIDER: S-EPMC6394855 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice.

Doke Tomohito T Ishimoto Takuji T Hayasaki Takahiro T Ikeda Satsuki S Hasebe Masako M Hirayama Akiyoshi A Soga Tomoyoshi T Kato Noritoshi N Kosugi Tomoki T Tsuboi Naotake N Lanaspa Miguel A MA Johnson Richard J RJ Kadomatsu Kenji K Maruyama Shoichi S

Metabolism: clinical and experimental 20180329

<h4>Objective</h4>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.<h4>Materials a ...[more]

PMID: 29604362

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Project description:Renal interstitial fibrosis is considered to be the typical manifestation of diabetic nephropathy (DN). Mangiferin has shown positive effect on the prevention or treatment of diabetes and its complications. The aim of this study was to explore the inhibitive effect and mechanism of mangiferin on renal interstitial fibrosis in diabetic mice. Streptozotocin- (STZ-) induced diabetic mice were treated with mangiferin (15, 30, and 60?mg/kg/d) for 4 weeks. The morphology of kidneys was observed by Masson's trichrome staining, and the biochemical parameters (fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), blood urea nitrogen (BUN), serum creatinine (SCr), and urine protein) were determined by kits. In addition, the levels of inflammatory cytokines (tumor necrosis factor-? (TNF-?), interleukin- (IL-) 6, and IL-1?), antioxidant enzymes (SOD, CAT, and GSH-Px), MDA, and ROS were assessed. Furthermore, the expressions of fibronectin (FN), collagen I (Col I), and ?-SMA were measured by immunohistochemistry. Regulations of TGF-?1 and the PTEN/PI3K/Akt pathway were detected by Western blotting. Treatment with mangiferin significantly ameliorated renal dysfunction in diabetic mice, as evidenced by the increase in body weight and decreases in FBG, TG, TC, BUN, SCr, urine protein, and the kidney to body weight ratio (KW/BW). Furthermore, mangiferin treatment prevented renal interstitial fibrosis evidenced by decreases in the positive expression of FN, Col I, and ?-SMA, in comparison with morphological changes in the renal tissue. Meanwhile, mangiferin increased antioxidant enzymes, reduced the TNF-?, IL-6, and IL-1?, as well as MDA and ROS. Additionally, mangiferin administration also downregulated TGF-?1, upregulated PTEN, and decreased the phosphorylation of both PI3K and Akt. These findings demonstrate that mangiferin may reduce inflammation and oxidative stress in DN, thereby inhibiting the renal interstitial fibrosis by reducing the TGF-?1-mediated elevation of Col I, FN, and ?-SMA through the PTEN/PI3K/Akt pathway.

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Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice.

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Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice.

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