Pichler R H, Franceschini N, Young B A, Hugo C, Andoh T F, Burdmann E A, Shankland S J, Alpers C E, Bennett W M, Couser W G
Division of Nephrology, University of Washington Medical Center, Seattle, USA.
J Am Soc Nephrol. 1995 Oct;6(4):1186-96. doi: 10.1681/ASN.V641186.
Low-salt-diet, cyclosporine (CsA; 15 mg/kg per day)-treated rats develop striped interstitial fibrosis, arteriolar hyalinosis, and azotemia similar to the chronic nephropathy observed in humans. To examine the role of angiotensin II in this model, rats on a low-salt diet were given CsA, CsA and the angiotensin II receptor Type I antagonist Losartan (10 mg/kg per day), CsA and hydralazine/furosemide, or vehicle. At Day 35, CsA-treated rats had tubular injury, arteriolopathy of the afferent arteriole, increased expression of the monocyte-macrophage adhesive protein osteopontin, interstitial macrophage infiltration, increased interstitial transforming growth factor-beta expression, and interstitial fibrosis. This study provides new insight in both pathogenic and therapeutic aspects of CsA nephropathy. The pathogenesis of CsA nephropathy involves the expression of osteopontin by tubular epithelial cells, the level of which closely correlates with the degree of macrophage infiltration and interstitial fibrosis in all groups (r = 0.79 and 0.74, respectively; P < 0.001). Therapeutic conclusions can be drawn from the observation that both losartan and hydralazine/furosemide reduced osteopontin expression, macrophage infiltration, transforming growth factor-beta expression, and interstitial fibrosis, but did not prevent the decrease in GFR. Treatment with losartan, but not with hydralazine and furosemide, markedly reduced arteriolopathy. It was concluded that angiotensin II contributes to the vasculopathy (hyalinosis) induced by CsA. In contrast, the interstitial fibrosis mediated by CsA can be partially prevented by both an angiotensin II Type I receptor antagonist or by hydralazine and furosemide. This suggests that the interstitial fibrosis can be dissociated from the vascular effects of CsA. The beneficial effects of lowering blood pressure or vasodilation per se may be difficult to distinguish from the specific effects of angiotensin II receptor blockade.
用低盐饮食、环孢素（CsA；每天15毫克/千克）治疗的大鼠会出现条纹状间质纤维化、小动脉玻璃样变性和氮质血症，类似于人类观察到的慢性肾病。为了研究血管紧张素II在该模型中的作用，给低盐饮食的大鼠分别给予CsA、CsA和血管紧张素II 1型受体拮抗剂氯沙坦（每天10毫克/千克）、CsA和肼屈嗪/呋塞米，或赋形剂。在第35天，用CsA治疗的大鼠出现肾小管损伤、入球小动脉的小动脉病、单核细胞 - 巨噬细胞粘附蛋白骨桥蛋白的表达增加、间质巨噬细胞浸润、间质转化生长因子 - β表达增加和间质纤维化。这项研究在CsA肾病的发病机制和治疗方面都提供了新的见解。CsA肾病的发病机制涉及肾小管上皮细胞骨桥蛋白的表达，其水平与所有组中巨噬细胞浸润程度和间质纤维化程度密切相关（分别为r = 0.79和0.74；P < 0.001）。从氯沙坦和肼屈嗪/呋塞米均降低骨桥蛋白表达、巨噬细胞浸润、转化生长因子 - β表达和间质纤维化，但未阻止肾小球滤过率降低这一观察结果可以得出治疗结论。用氯沙坦治疗，但不用肼屈嗪和呋塞米治疗，可显著减轻小动脉病。得出的结论是，血管紧张素II促成了CsA诱导的血管病（玻璃样变性）。相比之下，血管紧张素II 1型受体拮抗剂或肼屈嗪和呋塞米均可部分预防CsA介导的间质纤维化。这表明间质纤维化可能与CsA的血管效应无关。降低血压或血管舒张本身的有益作用可能难以与血管紧张素II受体阻断的特异性作用区分开来。
