Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
PLoS One. 2012;7(9):e45628. doi: 10.1371/journal.pone.0045628. Epub 2012 Sep 19.
Fibrinogen (Fg) has been recognized to play a central role in coagulation, inflammation and tissue regeneration. Several studies have used Fg deficient mice (Fg(-/-)) in comparison with heterozygous mice (Fg(+/-)) to point the proinflammatory role of Fg in diverse pathological conditions and disease states. Although Fg(+/-) mice are considered 'normal', plasma Fg is reduced to ~75% of the normal circulating levels present in wild type mice (Fg(+/+)). We report that this reduction in Fg protein production in the Fg(+/-) mice is enough to protect them from kidney ischemia reperfusion injury (IRI) as assessed by tubular injury, kidney dysfunction, necrosis, apoptosis and inflammatory immune cell infiltration. Mechanistically, we observed binding of Fg to ICAM-1 in kidney tissues of Fg(+/+) mice at 24 h following IRI as compared to a complete absence of binding observed in the Fg(+/-) and Fg(-/-) mice. Raf-1 and ERK were highly activated as evident by significantly higher phosphorylation in the Fg(+/+) kidneys at 24 h following IRI as compared to Fg(+/-) and Fg(-/-) mice kidneys. On the other hand Cyclin D1 and pRb, indicating higher cell proliferation, were significantly increased in the Fg(+/-) and Fg(-/-) as compared to Fg(+/+) kidneys. These data suggest that Fg heterozygosity allows maintenance of a critical balance of Fg that enables regression of initial injury and promotes faster resolution of kidney damage.
纤维蛋白原（Fg）在凝血、炎症和组织再生中起着核心作用。几项研究使用纤维蛋白原缺陷型（Fg(-/-)）小鼠与杂合子（Fg(+/-)）小鼠进行比较，以指出纤维蛋白原在多种病理条件和疾病状态下的促炎作用。尽管 Fg(+/-) 小鼠被认为是“正常”的，但血浆 Fg 减少到野生型（Fg(+/+)）小鼠正常循环水平的约 75%。我们报告称，Fg(+/-) 小鼠中 Fg 蛋白产生的这种减少足以保护它们免受肾缺血再灌注损伤（IRI），这可以通过肾小管损伤、肾功能障碍、坏死、凋亡和炎症免疫细胞浸润来评估。从机制上讲，我们观察到在 IRI 后 24 小时，Fg 在 Fg(+/+) 小鼠的肾脏组织中与 ICAM-1 结合，而在 Fg(+/-) 和 Fg(-/-) 小鼠中则完全没有观察到结合。Raf-1 和 ERK 被高度激活，这在 IRI 后 24 小时的 Fg(+/+) 肾脏中明显比 Fg(+/-)和 Fg(-/-) 肾脏中的磷酸化更高得到证实。另一方面，Cyclin D1 和 pRb，表明更高的细胞增殖，在 Fg(+/-) 和 Fg(-/-) 肾脏中与 Fg(+/+) 肾脏相比显著增加。这些数据表明，纤维蛋白原杂合性允许维持纤维蛋白原的关键平衡，从而使初始损伤得以恢复，并促进肾脏损伤更快地恢复。
