Shihab F S, Andoh T F, Tanner A M, Bennett W M
Division of Nephrology, University of Utah, and Department of Veterans Affairs Medical Center, Salt Lake City 84132, USA.
Am J Kidney Dis. 1997 Jul;30(1):71-81. doi: 10.1016/s0272-6386(97)90567-9.
The major limitation to the clinical use of cyclosporine (CsA) is renal toxicity. In the past, the lack of an animal model of chronic CsA nephropathy has hampered the study of its pathogenesis. Rats given CsA and placed on a low sodium diet (LSD) develop a histology similar to human lesions of chronic CsA nephropathy, a phenomenon not observed in animals on a normal sodium diet (NSD). We have previously shown that transforming growth factor-beta1 (TGF-beta1) is involved in the CsA-induced renal fibrosis in rats on a LSD. We hypothesized that sodium depletion is critical to the increase in TGF-beta1 expression, which, in turn, results in excessive matrix accumulation. Pair-fed rats were placed on a NSD or LSD, treated with CsA or vehicle, and killed at 7 or 28 days (N = 4 to 6 in each group). All rats achieved similar blood pressure control, and all CsA-treated rats achieved similar CsA blood levels. However, while CsA did not affect creatinine clearance in rats on a NSD, it lowered creatinine clearance in rats on a LSD (P < 0.01). Cyclosporine-induced tubulointerstitial fibrosis and arteriolopathy was observed at 28 days only in the rats on a LSD (P < 0.05). In addition, peripheral renin activity was increased only in the rats on a LSD (P < 0.01), while it remained normal in the rats on a NSD. In addition, CsA-treated rats on a LSD developed a progressive increase in the mRNA expression of TGF-beta1 and the matrix proteins biglycan and type I collagen at 7 and 28 days. Most of the changes were seen at 28 days (P < 0.001 for TGF-beta1, P < 0.01 for biglycan and type I collagen). On the other hand, CsA treatment in rats on a NSD did not affect the mRNA expression of TGF-beta1 and matrix proteins. Most of the changes in the immunofluorescence deposition of the glycoproteins tenascin and fibronectin EDA+ were in the tubulointerstitium and vessels of the kidneys of rats on a LSD and were mostly significant at 28 days, in accordance with the characteristic histology of chronic CsA nephropathy. The mRNA expression of plasminogen activator inhibitor-1, a protease inhibitor involved in matrix degradation and stimulated by TGF-beta1, was observed only in kidneys of rats on a LSD (P < 0.01). Since sodium depletion elevates peripheral renin activity, our experiments suggest a role for the renin-angiotensin system in the expression of TGF-beta1 and matrix proteins in CsA-induced renal fibrosis of rats on a LSD.
环孢素（CsA）临床应用的主要限制是肾毒性。过去，缺乏慢性CsA肾病的动物模型阻碍了其发病机制的研究。给予CsA并置于低钠饮食（LSD）的大鼠会出现与人类慢性CsA肾病病变相似的组织学变化，而正常钠饮食（NSD）的动物则未观察到这种现象。我们之前已经表明，转化生长因子-β1（TGF-β1）参与了LSD喂养大鼠中CsA诱导的肾纤维化。我们推测钠缺乏对于TGF-β1表达的增加至关重要，而这反过来又导致过多的基质积累。将配对喂养的大鼠置于NSD或LSD，用CsA或赋形剂处理，并在7天或28天时处死（每组N = 4至6）。所有大鼠的血压控制情况相似，所有接受CsA治疗的大鼠的CsA血药浓度也相似。然而，虽然CsA对NSD喂养的大鼠的肌酐清除率没有影响，但它降低了LSD喂养大鼠的肌酐清除率（P < 0.01）。仅在LSD喂养的大鼠中在28天时观察到CsA诱导的肾小管间质纤维化和小动脉病变（P < 0.05）。此外，仅在LSD喂养的大鼠中外周肾素活性增加（P < 0.01），而在NSD喂养的大鼠中其保持正常。此外，LSD喂养的CsA处理大鼠在7天和28天时TGF-β1、基质蛋白双糖链蛋白聚糖和I型胶原蛋白的mRNA表达逐渐增加。大多数变化在28天时出现（TGF-β1为P < 0.001，双糖链蛋白聚糖和I型胶原蛋白为P < 0.01）。另一方面，NSD喂养的大鼠接受CsA治疗不影响TGF-β1和基质蛋白的mRNA表达。糖蛋白肌腱蛋白和纤连蛋白EDA +的免疫荧光沉积变化大多发生在LSD喂养大鼠肾脏的肾小管间质和血管中，并且大多在28天时显著，这与慢性CsA肾病的特征性组织学一致。纤溶酶原激活物抑制剂-1（一种参与基质降解并受TGF-β1刺激的蛋白酶抑制剂）的mRNA表达仅在LSD喂养的大鼠肾脏中观察到（P < 0.01）。由于钠缺乏会升高外周肾素活性，我们的实验表明肾素-血管紧张素系统在LSD喂养大鼠的CsA诱导肾纤维化中TGF-β1和基质蛋白的表达中起作用。
