Suppression of Mitochondrial Biogenesis through Toll-Like Receptor 4-Dependent Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling in Endotoxin-Induced Acute Kidney Injury
Suppression of Mitochondrial Biogenesis through Toll-Like Receptor 4-Dependent Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling in Endotoxin-Induced Acute Kidney Injury
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DOI：
10.1124/jpet.114.221085
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发表时间：
2015-02-01
影响因子：
3.5
通讯作者：
Schnellmann, Rick G.
中科院分区：
文献类型：
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作者：
Smith, Joshua A.;Stallons, L. Jay;Schnellmann, Rick G.
虽然线粒体稳态和生物发生（MB）的破坏是脓毒症诱导的急性肾损伤（阿基）的一个广泛接受的病理生理学特征，负责这种现象的分子机制是未知的。在这项研究中，我们研究了负责抑制MB在脂多糖（LPS）诱导的阿基小鼠模型的信号通路。过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1 α）是MB的主要调节因子，在肾皮质中，在3小时的mRNA水平和18小时的蛋白水平上观察到其下调，并与LPS治疗后的肾功能丧失相关。LPS介导的PGC-1 α抑制导致MB和电子传递链蛋白下游调节因子的表达降低，同时沿着肾皮质线粒体DNA含量降低。从机制上讲，Toll样受体4（TLR 4）敲除小鼠在LPS暴露后免受肾损伤和MB破坏。免疫印迹分析显示LPS激活了肾皮质中的肿瘤进展位点2/丝裂原活化蛋白激酶激酶/细胞外信号调节激酶（TPL-2/MEK/ERK）信号传导。MEK/ERK信号传导的药理学抑制减轻了肾功能障碍和PGC-1 α的损失，并且与促炎细胞因子（例如，肿瘤坏死因子-α [TNF-α]，白细胞介素-1 β）表达。在LPS诱导的阿基后，TNF-α的中和也阻断了PGC-1 α的抑制，但没有肾功能障碍。最后，单独全身给予重组肿瘤坏死因子-α足以产生阿基并破坏线粒体稳态。这些发现表明TLR 4/MEK/ERK通路在LPS诱导的肾功能障碍和MB抑制中起重要作用。TLR 4/MEK/ERK/TNF-α信号转导可能是预防败血症引起的线粒体功能障碍和阿基的新的治疗靶点。
Although disruption of mitochondrial homeostasis and biogenesis (MB) is a widely accepted pathophysiologic feature of sepsis-induced acute kidney injury (AKI), the molecular mechanisms responsible for this phenomenon are unknown. In this study, we examined the signaling pathways responsible for the suppression of MB in a mouse model of lipopolysaccharide (LPS)-induced AKI. Downregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), a master regulator of MB, was noted at the mRNA level at 3 hours and protein level at 18 hours in the renal cortex, and was associated with loss of renal function after LPS treatment. LPS-mediated suppression of PGC-1 alpha led to reduced expression of downstream regulators of MB and electron transport chain proteins along with a reduction in renal cortical mitochondrial DNA content. Mechanistically, Toll-like receptor 4 (TLR4) knockout mice were protected from renal injury and disruption of MB after LPS exposure. Immunoblot analysis revealed activation of tumor progression locus 2/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (TPL-2/MEK/ERK) signaling in the renal cortex by LPS. Pharmacologic inhibition of MEK/ERK signaling attenuated renal dysfunction and loss of PGC-1 alpha, and was associated with a reduction in proinflammatory cytokine (e.g., tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta) expression at 3 hours after LPS exposure. Neutralization of TNF-alpha also blocked PGC-1 alpha suppression, but not renal dysfunction, after LPS-induced AKI. Finally, systemic administration of recombinant tumor necrosis factor-alpha alone was sufficient to produce AKI and disrupt mitochondrial homeostasis. These findings indicate an important role for the TLR4/MEK/ERK pathway in both LPS-induced renal dysfunction and suppression of MB. TLR4/MEK/ERK/TNF-alpha signaling may represent a novel therapeutic target to prevent mitochondrial dysfunction and AKI produced by sepsis.