Stanniocalcin-1: New paradigms for cytoprotection and anti-inflammation

总结 活性氧（ROS）、内皮损伤和巨噬细胞在缺血/再灌注损伤中起重要作用 （I/R）肾损伤。我们的数据显示斯钙素-1（STC 1）减少了巨噬细胞中超氧化物的产生， 通过诱导解偶联蛋白-2（UCP 2），降低巨噬细胞对 化学引诱物-和穿过内皮单层的迁移。在培养的内皮细胞中，STC 1保留了 屏障功能STC 1：减少超氧化物生成;抑制胡萝卜素诱导的Jun-N- 末端激酶（JNK）和紧密连接蛋白表达的丧失。STC 1转基因小鼠，其表现出 升高的血清水平和STC 1在巨噬细胞和内皮细胞中的优先表达，显示 抗I/R肾损伤。总体假设：STC 1通过以下方式保护I/R肾损伤：抑制 维持I/R肾损伤后正常的内皮屏障功能;以及 抑制巨噬细胞。在目的I中，我们将确定超氧化物和Daxx在STC 1介导的细胞凋亡中的作用。 内皮细胞中JNK的抑制。在目标II中，我们将确定STC 1对 缺氧/复氧（H/RO）诱导的紧密连接蛋白表达和组装的变化， 培养的原代肾内皮细胞。在I/R肾损伤的背景下，目标III将检查 大分子的内皮渗漏、肾脏炎症和肾内皮特异性或 巨噬细胞特异性过表达或缺失STC 1。目前几乎没有治疗选择可用于 急性肾损伤（阿基）。我们的数据确定STC 1作为缺血性损伤的潜在治疗靶点， 肾脏和其他器官，我们提出的研究将进一步阐明STC 1的作用机制。

Summary Reactive oxygen species (ROS), endothelial injury and macrophages play critical roles in ischemia/reperfusion (I/R) kidney injury. Our data show stanniocalcin-1 (STC1) diminishes superoxide generation in macrophages, through induction of uncoupling protein-2 (UCP2), decreases the response of macrophages to chemoattractants- and migration across an endothelial monolayer. In cultured endothelial cells, STC1 preserve barrier function. STC1: diminishes superoxide generation; inhibits cytokine-induced activation of Jun-N- terminal kinase (JNK) and loss of tight junction proteins expression. STC1 transgenic mice, which exhibit elevated serum levels and preferential expression of STC1 in macrophages and endothelium, display resistance to I/R kidney injury. Overall hypothesis: STC1 protects from I/R kidney injury through: suppression of superoxide generation; maintenance of normal endothelial barrier function following I/R kidney injury; and inhibition of macrophages. In Objective I, we will determine the role of superoxide and Daxx in STC1-mediated inhibition of JNK in endothelial cells. In Objective II, we will determine the effect of STC1 on hypoxia/reoxygenation (H/RO)-induced changes in the expression and assembly of tight junction proteins in cultured primary kidney endothelial cells. In the context of I/R kidney injury, Objective III will examine endothelial leakage to macromolecules, kidney inflammation and function after kidney endothelium-specific or macrophage-specific overexpression or deletion of STC1. Few therapeutic options are currently available for acute kidney injury (AKI). Our data identify STC1 as a potential therapeutic target for ischemic injury in the kidney and other organs, and our proposed studies will further elucidate STC1 mechanisms of action.