Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression.
Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression.
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自噬限制内毒素急性肾损伤，并改变肾小管上皮细胞因子表达。
DOI：
10.1371/journal.pone.0150001
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Ross MJ
中科院分区：
文献类型：
--
作者：
Leventhal JS;Ni J;Osmond M;Lee K;Gusella GL;Salem F;Ross MJ
脓毒症相关急性肾损伤（阿基）是一种常见的院内并发症，预后不良。我们对疾病发病机制的不完全理解阻碍了假设驱动的预防或治疗干预措施的确定。在阿基的缺血-再灌注和肾毒性小鼠模型中，越来越多的证据支持自噬保护肾小管上皮细胞（RTEC）免受损伤的理论。然而，RTEC自噬在脓毒症阿基中的作用仍不清楚。我们观察到，脂多糖（LPS），革兰氏阴性细菌脓毒症的介质，诱导RTEC自噬在体内和体外通过TLR 4启动的信号。我们通过腹腔内注射LPS在小鼠中模拟脓毒性阿基，其中自噬相关蛋白7在肾近端小管中被特异性敲除（ATG 7 KO）。与对照同窝仔相比，ATG 7 KO小鼠发生了更严重的肾功能不全（24小时BUN 100.1 mg/dl +/- 14.8 vs 54.6 mg/dl +/- 11.3）和实质损伤。在注射LPS后，肾裂解物的分析鉴定了与对照相比，来自ATG 7 KO小鼠的肾裂解物中更高的IL-6表达和增加的STAT 3活化。体外实验证实，在具有自噬的遗传或药理学损伤的RTEC中，对LPS的反应改变。总之，RTEC自噬保护免受内毒素诱导的损伤并调节RTEC TLR 4信号传导的下游效应。
Sepsis related acute kidney injury (AKI) is a common in-hospital complication with a dismal prognosis. Our incomplete understanding of disease pathogenesis has prevented the identification of hypothesis-driven preventive or therapeutic interventions. Increasing evidence in ischemia-reperfusion and nephrotoxic mouse models of AKI support the theory that autophagy protects renal tubular epithelial cells (RTEC) from injury. However, the role of RTEC autophagy in septic AKI remains unclear. We observed that lipopolysaccharide (LPS), a mediator of gram-negative bacterial sepsis, induces RTEC autophagy in vivo and in vitro through TLR4-initiated signaling. We modeled septic AKI through intraperitoneal LPS injection in mice in which autophagy-related protein 7 was specifically knocked out in the renal proximal tubules (ATG7KO). Compared to control littermates, ATG7KO mice developed more severe renal dysfunction (24hr BUN 100.1mg/dl +/- 14.8 vs 54.6mg/dl +/- 11.3) and parenchymal injury. After injection with LPS, analysis of kidney lysates identified higher IL-6 expression and increased STAT3 activation in kidney lysates from ATG7KO mice compared to controls. In vitro experiments confirmed an altered response to LPS in RTEC with genetic or pharmacological impairment of autophagy. In conclusion, RTEC autophagy protects against endotoxin induced injury and regulates downstream effects of RTEC TLR4 signaling.
影响因子：
3.7
作者：
Leventhal JS;Alsauskas Z;Snyder A;Gong P;Wang B;D'Agati V;Ross MJ
通讯作者：
Ross MJ