Oikawa T, Freeman M, Lo W, Vaughan D E, Fogo A
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Kidney Int. 1997 Jan;51(1):164-72. doi: 10.1038/ki.1997.20.
We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.
我们研究了在大鼠辐射损伤后内皮损伤和硬化情况下，纤溶酶原激活物抑制剂-1（PAI-1）与血管紧张素II（Ang II）在体内的联系潜力。PAI-1是纤溶酶原激活物（PA）/纤溶酶系统的主要生理抑制剂，是纤维蛋白溶解和细胞外基质（ECM）周转的关键调节因子。照射后12周，肾脏中PAI-1 mRNA表达显著增加（9倍）（与正常对照组相比，P < 1.001）。原位杂交显示PAI-1表达与肾小球损伤部位显著相关（损伤肾小球与完整肾小球的信号强度相比，P < 0.001）。血管紧张素转换酶抑制剂（ACEI，卡托普利或依那普利）或血管紧张素II受体拮抗剂（AIIRA，L158,809）显著减少了肾小球病变（血栓形成、系膜溶解和硬化；硬化指数，0至4+分级，未治疗组为0.49±0.20，卡托普利、依那普利和AIIRA组分别为0.05±0.02、0.02±0.01、0.04±0.02，与未治疗组相比，所有P < 0.01）。此外，ACEI和AIIRA显著减弱了照射肾脏中PAI-1 mRNA表达的增加（卡托普利、依那普利和AIIRA组的表达分别为36%、19%和20%，与未治疗的照射肾脏相比，P < 0.05、< 0.01、< 0.01）。这种作用具有选择性，因为组织型和尿激酶型PA mRNA表达均不受这些干预措施的影响。因此，我们推测抑制肾素-血管紧张素系统可能至少部分通过抑制PAI-1表达来加速纤维蛋白溶解和ECM降解，从而改善辐射后的损伤。总之，抑制Ang II除了其对血管硬化的已知作用外，还可能通过其抑制PAI-1的新作用减轻内皮/血栓形成损伤后的纤维化。
