Watanabe Daisuke, Tanabe Akiyo, Naruse Mitsuhide, Morikawa Shunichi, Ezaki Taichi, Takano Kazue
Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Tokyo, Japan.
Hypertens Res. 2009 Sep;32(9):807-15. doi: 10.1038/hr.2009.106. Epub 2009 Aug 7.
Metabolic syndrome (MS) is an independent risk factor for chronic kidney diseases. As the renin-angiotensin system (RAS) is known to have a key role in renal damage, blockade of RAS may show renoprotective effects in MS. In this study, we investigated the renoprotective effects and mechanisms of action of an angiotensin receptor blocker (ARB) in spontaneously hypertensive (SHR/NDmcr-cp) rats as a model of MS. Male SHR/NDmcr-cp rats at 9 weeks of age were divided into three groups, each of which was treated for 12 weeks with vehicle, hydralazine (7.5 mg kg(-1) per day, p.o.) or ARB (olmesartan, 5 mg kg(-1) per day, p.o.). Blood pressure and urinary protein (UP) excretion were monitored. Kidney tissues were subjected to histological, immunohistochemical and molecular analyses. UP excretion increased with age in vehicle-treated SHR/NDmcr-cp rats compared with that in age-matched WKY/Izm rats. In addition, there was significant glomerular damage (increased glomerular sclerosis index, desmin staining and proliferating cell nuclear antigen (PCNA)-positive cells, electron microscopic findings of podocyte injury) and tubulointerstitial damage (increased tubulointerstitial fibrosis index, type IV collagen staining, PCNA-positive cells and expression of TGF-beta mRNA) in vehicle-treated SHR/NDmcr-cp rats compared with that in control rats. All the findings that related to glomerular and tubulointerstitial damage were significantly improved by ARB. Hydralazine mitigated the observed renal damage but was much less effective than ARB, despite similar decreases in blood pressure. There were no significant differences in glucose and lipid metabolism among vehicle-treated, hydralazine-treated and ARB-treated SHR/NDmcr-cp animals. These data suggest that RAS is deeply involved in the pathogenesis of renal damage in MS, and ARBs could provide a powerful renoprotective regimen for patients with MS.
代谢综合征（MS）是慢性肾脏病的独立危险因素。由于已知肾素-血管紧张素系统（RAS）在肾损伤中起关键作用，阻断RAS可能对MS具有肾脏保护作用。在本研究中，我们以MS模型自发性高血压（SHR/NDmcr-cp）大鼠为研究对象，探讨了血管紧张素受体阻滞剂（ARB）的肾脏保护作用及其作用机制。将9周龄的雄性SHR/NDmcr-cp大鼠分为三组，每组分别给予赋形剂、肼屈嗪（7.5 mg·kg⁻¹·d⁻¹，口服）或ARB（奥美沙坦，5 mg·kg⁻¹·d⁻¹，口服）治疗12周。监测血压和尿蛋白（UP）排泄情况。对肾脏组织进行组织学、免疫组织化学和分子分析。与年龄匹配的WKY/Izm大鼠相比，给予赋形剂的SHR/NDmcr-cp大鼠的UP排泄量随年龄增加。此外，与对照大鼠相比，给予赋形剂的SHR/NDmcr-cp大鼠存在明显的肾小球损伤（肾小球硬化指数增加、结蛋白染色和增殖细胞核抗原（PCNA）阳性细胞增加、足细胞损伤的电子显微镜观察结果）和肾小管间质损伤（肾小管间质纤维化指数增加、IV型胶原染色、PCNA阳性细胞和TGF-β mRNA表达增加）。ARB显著改善了所有与肾小球和肾小管间质损伤相关的结果。肼屈嗪减轻了观察到的肾损伤，但尽管血压下降相似，其效果远不如ARB。在给予赋形剂、肼屈嗪和ARB治疗的SHR/NDmcr-cp动物中，葡萄糖和脂质代谢没有显著差异。这些数据表明，RAS深度参与MS肾损伤的发病机制，ARB可为MS患者提供强大的肾脏保护方案。
