Department of Nephrology, University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil.
PLoS One. 2012;7(1):e29893. doi: 10.1371/journal.pone.0029893. Epub 2012 Jan 3.
Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI.
RATS WERE RANDOMIZED INTO THREE GROUPS: control; CLP; and CLP+CERA (5 µg/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting--to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-κB)--and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1β, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection.
Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-κB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats.
CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.
尽管支持治疗取得了进展，但与败血症相关的死亡率仍然很高，尤其是在急性肾损伤（AKI）患者中。促红细胞生成素可保护器官免受缺血和败血症的影响。这种作用与细胞内生存途径的激活有关，但机制尚不清楚。连续促红细胞生成素受体激活剂（CERA）是一种具有独特药理学特性和长半衰期的促红细胞生成素。我们假设 CERA 预处理将在盲肠结扎和穿刺（CLP）诱导的败血症性 AKI 模型中具有肾保护作用。
大鼠随机分为三组：对照组；CLP 组；CLP+CERA 组（5µg/kg 体重，腹腔注射，CLP 前 24 小时给药）。CLP 后 24 小时，我们测量肌酐清除率、生化变量和血流动力学参数。在肾组织中，我们进行了免疫印迹分析——以定量测定钠钾 2 氯共转运蛋白（NKCC2）、水通道蛋白 2（AQP2）、Toll 样受体 4（TLR4）、促红细胞生成素受体（EpoR）和核因子 kappa B（NF-κB）的表达——以及 CD68（巨噬细胞浸润）的免疫组织化学染色。通过多重检测测量血浆白细胞介素（IL）-2、IL-1β、IL-6、IL-10、干扰素 γ 和肿瘤坏死因子-α。
CERA 预处理可维持肌酐清除率和肾小管功能，以及 NKCC2 和 AQP2 的表达。此外，CERA 使血浆乳酸保持在正常水平，并维持血浆转氨酶和乳酸脱氢酶水平。CLP+CERA 大鼠的肾 TLR4 和 NF-κB 表达低于 CLP 大鼠（分别为 p<0.05 和 p<0.01），CD68 阳性细胞计数也较低（p<0.01），而肾 EpoR 表达较高（p<0.05）。CLP+CERA 大鼠的所有测定细胞因子的血浆水平均低于 CLP 大鼠。
CERA 可预防败血症性 AKI。这种保护作用部分归因于炎症反应的抑制。
