Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice.
Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice.
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缺乏酮己激酶-A加剧链蛋白酶诱导的糖尿病小鼠的肾脏损伤。
DOI：
10.1016/j.metabol.2018.03.020
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Maruyama S
中科院分区：
文献类型：
--
作者：
Doke T;Ishimoto T;Hayasaki T;Ikeda S;Hasebe M;Hirayama A;Soga T;Kato N;Kosugi T;Tsuboi N;Lanaspa MA;Johnson RJ;Kadomatsu K;Maruyama S
酮己糖激酶（KHK）是果糖代谢的主要酶，有两种异构体，即KHK-A和KHK-C。以前，我们报道了在缺乏这两种亚型的链脲佐菌素诱导的糖尿病小鼠中肾损伤减少。虽然这两种亚型在肾脏中表达，但尚未阐明每种亚型是否在糖尿病肾病（DKD）的发展中发挥不同的作用。本研究的目的是阐明KHK-A在DKD进展中的作用。通过在C57 BL/6 J野生型小鼠、仅缺乏KHK-A的小鼠（KHK-A KO）和缺乏KHK-A和KHK-C两者的小鼠（KHK-A/C KO）中连续5天每天腹膜内注射链脲佐菌素（50 mg/kg）来诱导糖尿病。在35周时，检查肾损伤、炎症、缺氧和氧化应激。代谢组学分析包括肾脏和尿液中的多元醇途径、果糖代谢、糖酵解、TCA（三羧酸）循环和NAD（烟酰胺腺嘌呤二核苷酸）代谢。与糖尿病野生型小鼠相比，糖尿病KHK-A KO小鼠发生了严重的肾损伤，这与肾内果糖、磷酸二羟丙酮（DHAP）、TCA循环中间体水平和严重炎症的进一步增加有关。相比之下，与野生型和KHK-A KO糖尿病小鼠相比，糖尿病KHK-A/C KO小鼠的肾损伤得到了预防。此外，糖尿病KHK-A KO小鼠尽管肾脏烟酰胺（NAM）水平增加，但肾脏NAD+水平降低，肾脏缺氧诱导因子1-α表达增加。这些结果表明，KHK-C可能通过内源性果糖代谢在DKD进展中起有害作用，并且KHK-A对DKD的发展起独特的保护作用。
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. 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. 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 intermediates 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. 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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影响因子：
3.4
作者：
Hurtado-Arestegui, Abdias;Plata-Cornejo, Raul;Pando, Jackelina
通讯作者：
Pando, Jackelina
影响因子：
4.6
作者：
de Oliveira AA;de Oliveira TF;Bobadilla LL;Garcia CC;Berra CM;de Souza-Pinto NC;Medeiros MH;Di Mascio P;Zatz R;de M Loureiro AP
通讯作者：
de M Loureiro AP
影响因子：
5.1
作者：
Gimenez-Dejoz, Joan;Weber, Susanne;Farres, Jaume
通讯作者：
Farres, Jaume
影响因子：
13.6
作者：
Cirillo, Pietro;Gersch, Michael S.;Sautin, Yuri Y.
通讯作者：
Sautin, Yuri Y.
影响因子：
19.6
作者：
Chow, F;Ozols, E;Tesch, GH
通讯作者：
Tesch, GH