Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
FASEB J. 2019 Oct;33(10):11528-11540. doi: 10.1096/fj.201900583R. Epub 2019 Aug 1.
Acute kidney injury (AKI) remains an important source of progressive chronic kidney injury. Loss of renal blood flow with subsequent restoration, termed ischemia reperfusion (IR), is a common cause of AKI. The cell surface receptor signal regulatory protein α (SIRP-α) is expressed on macrophages and limits inflammation and phagocytosis. SIRP-α has recently been found to have wider cell-based expression and play a role in renal IR. We have explored this in a genetic model of deficient SIRP-α signaling. Mice lacking SIRP-α cytoplasmic signaling (SIRP-α) and wild-type (WT) littermate controls underwent renal ischemia and reperfusion. Chimeric mice transplanted with WT or SIRP-α bone marrow were similarly challenged following engraftment. Molecular and immunohistochemical analysis of renal function, tissue damage, and key molecular targets was performed. SIRP-α mice were protected from renal IR compared with WT animals, demonstrating improved serum creatinine, less histologic damage, reduced proinflammatory cytokine production, and diminished production of reactive oxygen species (ROS). Resistance to renal IR in SIRP-α occurred alongside down-regulation of CD47 and thrombospondin-1, which are known to exert SIRP-α crosstalk and also promote IR. In chimeric mice, lack of SIRP-α signaling conferred protection to IR regardless of the genotype of circulating cells. Renal tubular epithelial cells from SIRP-α mice produced fewer ROS and proinflammatory cytokines . These results identify parenchymal SIRP-α as an independent driver of IR-mediated AKI and a potential therapeutic target.-Ghimire, K., Chiba, T., Minhas, N., Meijles, D. N., Lu, B., O'Connell, P., Rogers, N. M. Deficiency in SIRP-α cytoplasmic recruitment confers protection from acute kidney injury.
急性肾损伤 (AKI) 仍然是慢性进行性肾损伤的重要原因。肾血流丢失后再灌注，即缺血再灌注 (IR)，是 AKI 的常见原因。细胞表面受体信号调节蛋白α (SIRP-α) 在巨噬细胞上表达，限制炎症和吞噬作用。最近发现 SIRP-α 具有更广泛的细胞表达，并在肾 IR 中发挥作用。我们在 SIRP-α 信号缺失的遗传模型中对此进行了探索。缺乏 SIRP-α 细胞质信号 (SIRP-α) 的小鼠和野生型 (WT) 同窝对照小鼠接受肾缺血再灌注。WT 或 SIRP-α 骨髓移植的嵌合小鼠在植入后也受到类似的挑战。对肾功能、组织损伤和关键分子靶点进行了分子和免疫组织化学分析。与 WT 动物相比，SIRP-α 小鼠对肾 IR 具有保护作用，表现为血清肌酐改善、组织损伤减少、促炎细胞因子产生减少和活性氧 (ROS) 产生减少。SIRP-α 下调 CD47 和血小板反应蛋白-1，这两种蛋白已知能发挥 SIRP-α 相互作用并促进 IR，SIRP-α 对肾 IR 的抵抗作用与循环细胞的基因型无关。SIRP-α 小鼠的肾小管上皮细胞产生的 ROS 和促炎细胞因子较少。这些结果表明，实质 SIRP-α 是 IR 介导的 AKI 的独立驱动因素，也是潜在的治疗靶点。-Ghimire，K.，Chiba，T.，Minhas，N.，Meijles，D. N.，Lu，B.，O'Connell，P.，Rogers，N. M. SIRP-α 细胞质募集缺陷赋予急性肾损伤保护作用。
