Heparanase mediates renal dysfunction during early sepsis in mice.
Heparanase mediates renal dysfunction during early sepsis in mice.
复制标题
DOI：
10.1002/phy2.153
复制
发表时间：
2013-11
影响因子：
2.5
通讯作者：
Schmidt, Eric P
中科院分区：
文献类型：
--
作者：
Lygizos, Melissa I;Yang, Yimu;Altmann, Christopher J;Okamura, Kayo;Hernando, Ana Andres;Perez, Mario J;Smith, Lynelle P;Koyanagi, Daniel E;Gandjeva, Aneta;Bhargava, Rhea;Tuder, Rubin M;Faubel, Sarah;Schmidt, Eric P
乙酰肝素酶是一种硫酸乙酰肝素特异性葡萄糖醛酸酶，在脓毒症早期介导肺中性粒细胞粘附和炎性肺损伤的发生。我们假设肾小球乙酰肝素酶在脓毒症中同样被激活，并导致脓毒症急性肾损伤（阿基）。我们在存在或不存在竞争性乙酰肝素酶抑制剂（肝素或非抗凝剂N-乙酰化再-N-乙酰化肝素[NAH]）的情况下，使用盲肠结扎穿孔（CLP）诱导小鼠多微生物败血症。手术后4小时，我们收集血清和尿液用于测量肾功能和全身炎症，侵入性地确定全身血流动力学，收获肾脏用于组织学/蛋白质/mRNA，和/或通过菊粉清除率测量肾小球滤过。CLP处理的小鼠表现出肾小球乙酰肝素酶的早期活化，同时肾小球滤过损失，如与假手术小鼠相比，血液尿素氮（BUN）增加>两倍和菊粉清除减少>50%（P < 0.05）所示。在CLP前2小时给予乙酰肝素酶抑制剂可减弱脓毒症诱导的肾小球滤过率降低，表明乙酰肝素酶激活可导致早期脓毒症性肾功能不全。肾小球乙酰肝素酶激活与肾中性粒细胞流入或血管通透性改变无关，与先前描述的肺乙酰肝素酶对脓毒症期间嗜中性粒细胞肺损伤的影响形成鲜明对比。NAH预处理可减弱CLP诱导的肾脏炎性基因（IL-6、TNF-α、IL-1β）表达。虽然血清炎症指标（KC、IL-6、TNF-α、IL-1β）不受NAH预处理的影响，但乙酰肝素酶抑制剂减弱了CLP诱导的血清IL-10升高。这些发现表明，肾小球乙酰肝素酶是活跃的脓毒症，并有助于脓毒症肾功能不全的机制不同的乙酰肝素酶介导的肺损伤。
Heparanase, a heparan sulfate-specific glucuronidase, mediates the onset of pulmonary neutrophil adhesion and inflammatory lung injury during early sepsis. We hypothesized that glomerular heparanase is similarly activated during sepsis and contributes to septic acute kidney injury (AKI). We induced polymicrobial sepsis in mice using cecal ligation and puncture (CLP) in the presence or absence of competitive heparanase inhibitors (heparin or nonanticoagulant N-desulfated re-N-acetylated heparin [NAH]). Four hours after surgery, we collected serum and urine for measurement of renal function and systemic inflammation, invasively determined systemic hemodynamics, harvested kidneys for histology/protein/mRNA, and/or measured glomerular filtration by inulin clearance. CLP-treated mice demonstrated early activation of glomerular heparanase with coincident loss of glomerular filtration, as indicated by a >twofold increase in blood urea nitrogen (BUN) and a >50% decrease in inulin clearance (P < 0.05) in comparison to sham mice. Administration of heparanase inhibitors 2 h prior to CLP attenuated sepsis-induced loss of glomerular filtration rate, demonstrating that heparanase activation contributes to early septic renal dysfunction. Glomerular heparanase activation was not associated with renal neutrophil influx or altered vascular permeability, in marked contrast to previously described effects of pulmonary heparanase on neutrophilic lung injury during sepsis. CLP induction of renal inflammatory gene (IL-6, TNF-α, IL-1β) expression was attenuated by NAH pretreatment. While serum inflammatory indices (KC, IL-6, TNF-α, IL-1β) were not impacted by NAH pretreatment, heparanase inhibition attenuated the CLP-induced increase in serum IL-10. These findings demonstrate that glomerular heparanase is active during sepsis and contributes to septic renal dysfunction via mechanisms disparate from heparanase-mediated lung injury.