Brown N J, Bradford J, Wang Z, Lea W, Ma L, Ma J, Vaughan D E, Fogo A B
Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602, USA.
Kidney Int. 2007 Jul;72(1):72-81. doi: 10.1038/sj.ki.5002268. Epub 2007 Apr 11.
Angiotensin (Ang) II stimulates plasminogen activator inhibitor-1 (PAI-1) expression in many cell types by mechanisms that are cell-type specific. We measured effects of Ang II or norepinephrine on PAI-1 expression in wild type (WT) and Ang type-1a receptor knockout mice (AT(1a)-/-) in the presence or absence of the non-specific AT(1) antagonist losartan. Ang II and norepinephrine increased systolic blood pressure equally, whereas losartan decreased the pressor response of the former but not the latter in WT mice. In AT(1a)-/- mice, baseline systolic blood pressure was lower with no effect of Ang II, norepinephrine, or losartan. Ang II stimulated PAI-1 expression in the heart, aorta, and kidney and markedly in the liver of WT mice. In AT(1a)-/- mice, Ang II-stimulated PAI-1 was significantly attenuated compared with the WT in the heart and aorta but significantly enhanced in the kidney. Losartan decreased the induction in the aorta and liver of WT, and in the kidney and liver of AT(1a)-/- mice. Norepinephrine increased PAI-1 expression in WT heart and aorta, and in AT(1a)-/- heart, kidney, and liver with no effect of losartan. Renal PAI-1 expression correlated with AT(1b) receptor mRNA. We conclude that Ang II stimulates PAI-1 expression in part through the AT(1b) receptor in the kidney and liver. Further, norepinephrine induces PAI-1 expression in vivo with AT(1a) receptor deficiency modulating the effect.
血管紧张素（Ang）II通过细胞类型特异性机制刺激多种细胞类型中的纤溶酶原激活物抑制剂-1（PAI-1）表达。我们在存在或不存在非特异性AT(1)拮抗剂氯沙坦的情况下，测量了Ang II或去甲肾上腺素对野生型（WT）和1a型血管紧张素受体基因敲除小鼠（AT(1a)-/-）中PAI-1表达的影响。Ang II和去甲肾上腺素对收缩压的升高作用相同，而氯沙坦可降低WT小鼠中Ang II的升压反应，但对去甲肾上腺素的升压反应无影响。在AT(1a)-/-小鼠中，基线收缩压较低，Ang II、去甲肾上腺素或氯沙坦对其均无影响。Ang II刺激WT小鼠心脏、主动脉和肾脏以及肝脏中PAI-1的表达。在AT(1a)-/-小鼠中，与WT小鼠相比，Ang II刺激的PAI-1在心脏和主动脉中显著减弱，但在肾脏中显著增强。氯沙坦降低了WT小鼠主动脉和肝脏以及AT(1a)-/-小鼠肾脏和肝脏中PAI-1的诱导表达。去甲肾上腺素增加了WT小鼠心脏和主动脉以及AT(1a)-/-小鼠心脏、肾脏和肝脏中PAI-1的表达，氯沙坦对此无影响。肾脏中PAI-1的表达与AT(1b)受体mRNA相关。我们得出结论，Ang II部分通过肾脏和肝脏中的AT(1b)受体刺激PAI-1表达。此外，去甲肾上腺素在体内诱导PAI-1表达，1a型血管紧张素受体缺乏可调节该作用。
