Department of Medicine, Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO
Denver Veterans Affairs Medical Center, Denver, CO.
J Lipid Res. 2018 Feb;59(2):380-390. doi: 10.1194/jlr.M082362. Epub 2017 Dec 11.
The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2α) enzyme directs a complex "eicosanoid storm" that accompanies the tissue response to injury. cPLA2α and its downstream eicosanoid mediators are also implicated in the pathogenesis of fibrosis in many organs, including the kidney. We aimed to determine the role of cPLA2α in bone marrow-derived cells in a murine model of renal fibrosis, unilateral ureteral obstruction (UUO). WT C57BL/6J mice were irradiated and engrafted with donor bone marrow from either WT mice [WT-bone marrow transplant (BMT)] or mice deficient in cPLA2α (KO-BMT). After full engraftment, mice underwent UUO and kidneys were collected 3, 7, and 14 days after injury. Using picrosirius red, collagen-3, and smooth muscle α actin staining, we determined that renal fibrosis was significantly attenuated in KO-BMT animals as compared with WT-BMT animals. Lipidomic analysis of homogenized kidneys demonstrated a time-dependent upregulation of pro-inflammatory eicosanoids after UUO; KO-BMT animals had lower levels of many of these eicosanoids. KO-BMT animals also had fewer infiltrating pro-inflammatory CD45+CD11b+Ly6C macrophages and reduced message levels of pro-inflammatory cytokines. Our results indicate that cPLA2α and/or its downstream mediators, produced by bone marrow-derived cells, play a major role in eicosanoid production after renal injury and in renal fibrinogenesis.
IV 组钙依赖性胞质型磷脂酶 A2（cPLA2α）酶指导伴随组织损伤的复杂“花生四烯酸风暴”。cPLA2α及其下游的花生四烯酸介质也与许多器官（包括肾脏）的纤维化发病机制有关。我们旨在确定钙依赖性胞质型磷脂酶 A2（cPLA2α）在单侧输尿管梗阻（UUO）小鼠肾脏纤维化模型中骨髓来源细胞中的作用。WT C57BL/6J 小鼠接受辐照并用 WT 小鼠（WT 骨髓移植（BMT））或缺乏 cPLA2α 的小鼠（KO-BMT）的供体骨髓进行移植。完全移植后，小鼠接受 UUO 并在损伤后 3、7 和 14 天收集肾脏。通过皮尔斯红、胶原-3 和平滑肌 α 肌动蛋白染色，我们发现 KO-BMT 动物的肾脏纤维化明显低于 WT-BMT 动物。对匀浆肾脏进行脂质组学分析表明，UUO 后促炎花生四烯酸的水平呈时间依赖性上调；KO-BMT 动物的许多这些花生四烯酸水平较低。KO-BMT 动物的浸润性促炎 CD45+CD11b+Ly6C 巨噬细胞数量减少，促炎细胞因子的 mRNA 水平降低。我们的结果表明，cPLA2α 和/或其下游介质由骨髓来源的细胞产生，在肾脏损伤后和肾脏纤维发生中在花生四烯酸产生中起主要作用。
