Department of Nephrology, Hannover Medical School, Hannover, Germany.
Kidney Int. 2011 Nov;80(10):1035-44. doi: 10.1038/ki.2011.214. Epub 2011 Jul 6.
Fibrinogen plays an important role in blood coagulation but its function extends far beyond blood clotting being involved in inflammation and repair. Besides these crucial functions it can also promote tissue fibrosis. To determine whether fibrinogen is involved in the development of renal tubulointerstitial fibrosis we utilized the profibrotic model of unilateral ureteral obstruction in fibrinogen-deficient mice. In the heterozygotes, obstruction was associated with a massive deposition of intrarenal fibrinogen. Fibrinogen deficiency provided significant protection from interstitial damage and tubular disruption, attenuated collagen accumulation, and greatly reduced de novo expression of α-smooth muscle actin in the obstructed kidney. While no differences were found in renal inflammatory cell infiltration, fibrinogen deficiency was associated with a significant reduction in interstitial cell proliferation, a hallmark of renal fibrosis. In vitro, fibrinogen directly stimulated renal fibroblast proliferation in a dose-dependent manner. This mitogenic effect of fibrinogen was mediated by at least three different cell surface receptors on renal fibroblasts: TLR2, TLR4, and ICAM-1. Thus, our study suggests that fibrinogen promotes renal fibrosis by triggering resident fibroblast proliferation.
纤维蛋白原在血液凝固中起着重要作用，但它的功能远不止于此，还参与炎症和修复。除了这些关键功能外，它还可以促进组织纤维化。为了确定纤维蛋白原是否参与了肾小管间质纤维化的发展，我们利用纤维蛋白原缺陷型小鼠的单侧输尿管梗阻致纤维化模型进行研究。在杂合子中，梗阻与大量的肾内纤维蛋白原沉积有关。纤维蛋白原缺陷显著减轻了间质损伤和肾小管破坏，胶原积累减少，并且显著降低了梗阻肾脏中α-平滑肌肌动蛋白的新表达。虽然肾炎性细胞浸润没有差异，但纤维蛋白原缺陷与间质细胞增殖显著减少有关，而间质细胞增殖是肾纤维化的一个标志。在体外，纤维蛋白原以剂量依赖性方式直接刺激肾成纤维细胞增殖。纤维蛋白原的这种有丝分裂作用是通过肾成纤维细胞上至少三种不同的细胞表面受体介导的：TLR2、TLR4 和 ICAM-1。因此，我们的研究表明，纤维蛋白原通过触发固有成纤维细胞增殖来促进肾纤维化。
