Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Am J Physiol Renal Physiol. 2013 Sep 1;305(5):F777-85. doi: 10.1152/ajprenal.00418.2012. Epub 2013 Jun 26.
Renal ischemia-reperfusion (I/R) is associated with activation of the coagulation system and accumulation of blood clotting factors in the kidney. The aim of the present study was to examine the functional impact of fibrinogen on renal inflammation, damage, and repair in the context of I/R injury. In this study, we found that I/R was associated with a significant increase in the renal deposition of circulating fibrinogen. In parallel, I/R stress induced the de novo expression of fibrinogen in tubular epithelial cells, as reflected by RT-PCR, immunofluorescence, and in situ hybridization. In vitro, fibrinogen expression was induced by oncostatin M and hyper-IL-6 in primary tubular epithelial cells, and fibrinogen-containing medium had an inhibitory effect on tubular epithelial cell adhesion and migration. Fibrinogen(+/-) mice showed similar survival as wild-type mice but better preservation in early postischemic renal function. In fibrinogen(-/-) mice, renal function and survival were significantly worse than in fibrinogen(+/-) mice. Renal transplant experiments revealed reduced expression of tubular damage markers and attenuated proinflammatory cytokine expression but increased inflammatory cell infiltrates and transforming growth factor-β expression in fibrinogen(-/-) isografts. These data point to heterogeneous effects of fibrinogen in renal I/R injury. While a complete lack of fibrinogen may be detrimental, partial reduction of fibrinogen in heterozygous mice can improve renal function and overall outcome.
肾缺血再灌注（I/R）与凝血系统的激活和血液凝固因子在肾脏中的积累有关。本研究旨在探讨纤维蛋白原在 I/R 损伤情况下对肾脏炎症、损伤和修复的功能影响。在这项研究中，我们发现 I/R 与循环纤维蛋白原在肾脏中的沉积显著增加有关。平行地，I/R 应激诱导肾小管上皮细胞中纤维蛋白原的新生表达，这反映在 RT-PCR、免疫荧光和原位杂交中。在体外，纤维蛋白原表达被oncostatin M 和高 IL-6 在原代肾小管上皮细胞中诱导，并且含纤维蛋白原的培养基对肾小管上皮细胞的黏附和迁移具有抑制作用。纤维蛋白原（+/-）小鼠的存活率与野生型小鼠相似，但在早期缺血后肾功能的保存方面更好。在纤维蛋白原（-/-）小鼠中，肾功能和存活率明显差于纤维蛋白原（+/-）小鼠。肾移植实验显示，纤维蛋白原（-/-）同种异体移植物中肾小管损伤标志物的表达减少，促炎细胞因子的表达减弱，但炎症细胞浸润和转化生长因子-β的表达增加。这些数据表明纤维蛋白原在肾 I/R 损伤中具有异质性作用。虽然完全缺乏纤维蛋白原可能是有害的，但杂合子小鼠中纤维蛋白原的部分减少可以改善肾功能和整体预后。
