Nerurkar S S, Olzinski A R, Frazier K S, Mirabile R C, O'Brien S P, Jing J, Rajagopalan D, Yue T L, Willette R N
Department of Investigative and Cardiac Biology, GlaxoSmithKline, King of Prussia, PA 119406, USA.
Biomarkers. 2007 Jan-Feb;12(1):87-112. doi: 10.1080/13547500600944930.
The assessment of target organ damage is important in defining the optimal treatment of hypertension and blood pressure-related cardiovascular disease. The aims of the present study were (1) to investigate candidate biomarkers of target organ damage, osteopontin (OPN) and plasminogen activator inhibitor-1 (PAI-1), in models of malignant hypertension with well characterized end-organ pathology; and (2) to evaluate the effects of chronic treatment with a p38 MAPK inhibitor. Gene expression, plasma concentrations, and renal immunohistochemical localization of OPN and PAI-1 were measured in stroke-prone spontaneously hypertensive rats on a salt-fat diet (SFD SHR-SP) and in spontaneously hypertensive rats receiving N(omega)-nitro-L-arginine methyl ester (L-NAME SHR). Plasma concentrations of OPN and PAI-1 increased significantly in SFD SHR-SP and L-NAME SHR as compared with controls, (2.5-4.5-fold for OPN and 2.0-9.0-fold for PAI-1). The plasma levels of OPN and PAI-1 were significantly correlated with the urinary excretion of albumin (p < 0.0001). Elevations in urinary albumin, plasma OPN and PAI-1 were abolished by chronic treatment (4-8 weeks) with a specific p38 MAPK inhibitor, SB-239063AN. OPN immunoreactivity was localized predominantly in the apical portion of tubule epithelium, while PAI-1 immunoreactivity was robust in glomeruli, tubules and renal artery endothelium. Treatment with the p38 MAPK inhibitor significantly reduced OPN and PAI-1 protein expression in target organs. Kidney gene expression was increased for OPN (4.9- and 7.9-fold) and PAI-1 (2.8- and 11.5-fold) in SFD SHR-SP and L-NAME SHR, respectively. In-silico pathway analysis revealed that activation of p38 MAPK was linked to OPN and PAI-1 via SPI, c-fos and c-jun; suggesting that these pathways may play an important role in p38 MAPK-dependent hypertensive renal dysfunction. The results suggest that enhanced OPN and PAI-1 expression reflects end-organ damage in hypertension and that suppression correlates with end-organ protection regardless of overt antihypertensive action.
评估靶器官损害对于确定高血压及血压相关心血管疾病的最佳治疗方案至关重要。本研究的目的是：（1）在具有明确终末器官病理特征的恶性高血压模型中，研究靶器官损害的候选生物标志物骨桥蛋白（OPN）和纤溶酶原激活物抑制剂-1（PAI-1）；（2）评估p38丝裂原活化蛋白激酶（MAPK）抑制剂的长期治疗效果。在接受盐-脂肪饮食的易中风自发性高血压大鼠（SFD SHR-SP）和接受N（ω）-硝基-L-精氨酸甲酯的自发性高血压大鼠（L-NAME SHR）中，测量OPN和PAI-1的基因表达、血浆浓度及肾脏免疫组化定位。与对照组相比，SFD SHR-SP和L-NAME SHR中OPN和PAI-1的血浆浓度显著升高（OPN升高2.5至4.5倍，PAI-1升高2.0至9.0倍）。OPN和PAI-1的血浆水平与尿白蛋白排泄显著相关（p<0.0001）。用特异性p38 MAPK抑制剂SB-239063AN进行长期治疗（4至8周）可消除尿白蛋白、血浆OPN和PAI-1的升高。OPN免疫反应主要定位于肾小管上皮的顶端部分，而PAI-1免疫反应在肾小球、肾小管和肾动脉内皮中较强。p38 MAPK抑制剂治疗显著降低了靶器官中OPN和PAI-1的蛋白表达。在SFD SHR-SP和L-NAME SHR中，肾脏基因表达中OPN分别升高4.9倍和7.9倍，PAI-1分别升高2.8倍和11.5倍。计算机通路分析显示，p38 MAPK的激活通过SPI、c-fos和c-jun与OPN和PAI-1相关联；表明这些通路可能在p38 MAPK依赖性高血压性肾功能障碍中起重要作用。结果表明，OPN和PAI-1表达增强反映了高血压中的终末器官损害，且抑制作用与终末器官保护相关，而与明显的降压作用无关。
