Effects of L-Carnitine Treatment on Kidney Mitochondria and Macrophages in Mice with Diabetic Nephropathy
Effects of L-Carnitine Treatment on Kidney Mitochondria and Macrophages in Mice with Diabetic Nephropathy
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DOI：
10.1159/000522013
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发表时间：
2022-04-01
影响因子：
2.8
通讯作者：
Oshima，Naoki
中科院分区：
文献类型：
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作者：
Ito，Seigo;Nakashima，Masahiro;Oshima，Naoki
糖尿病肾病(DN)患者线粒体功能障碍和线粒体DNA(MtDNA)漏失是由超氧化物歧化酶2(SOD2)表达下调引起的。线粒体DNA可诱导巨噬细胞(MφS)Toll样受体9的激活，并激活巨噬细胞。方法对肥胖糖尿病肾病(db/db)小鼠灌胃给予具有线粒体保护作用的L肉碱8周。结果db/db小鼠近端肾小管上皮细胞线粒体φ生成增加，肾脏CD11b低Mφ表达增加，而肾脏CD11b低Mφ表达增强。L-卡尼汀可抑制肾小管上皮细胞和CD11b低MφS肾小管上皮细胞线粒体ROS的生成，改善肾脏组织中SOD2的表达(P<0.01)，降低循环中线粒体DNA含量，减少蛋白尿。此外，它还能抑制Mφ向肾脏的渗透，减少MφS TLR9的表达(P<0.0 1)，从而降低CD11b高MαS(P<0.0 5)和CD11b低MφS(P<0.0 1)产生的ROS。结论L肉碱对糖尿病肾病的积极治疗作用提示其有望成为治疗肥胖相关性糖尿病肾病的新药物。
IntroductionIn diabetic nephropathy (DN), mitochondrial dysfunction and leakage of mitochondrial DNA (mtDNA) are caused by the downregulation of superoxide dismutase 2 (SOD2). mtDNA induces the activation of Toll-like receptor (TLR) 9, which is present in macrophages (Mφs), and triggers their activation.MethodsWe orally administered L-carnitine, which exerts protective effects on the mitochondria, to obesity-induced DN (db/db) mice for 8 weeks. We then investigated the effects of L-carnitine on kidney mitochondrial reactive oxygen species (mtROS) production, circulating mtDNA content, and kidney CD11b high/CD11b low Mφ functions.ResultsIn db/db mice, mtROS production increased in proximal tubular cells and kidney CD11b low Mφs; both Mφ types showed enhanced TLR9 expression. L-Carnitine treatment suppressed mtROS production in both proximal tubular cells and CD11b low Mφs (p< 0.01), with improved SOD2 expression in the kidney (p< 0.01), decreased circulating mtDNA content, and reduced albuminuria. Moreover, it suppressed Mφ infiltration into kidneys and reduced TLR9 expression in Mφs (p< 0.01), thereby lowering tumor necrosis factor-α production in CD11b high Mφs (p< 0.05) and ROS production by CD11b low Mφs (p< 0.01). Collectively, these changes alleviated DN symptoms.ConclusionThe positive effects of L-carnitine on DN suggest its potential as a novel therapeutic agent against obesity-linked DN.