Therapeutic role of TGF-β-neutralizing antibody in mouse cyclosporin a nephropathy:: Morphologic improvement associated with functional preservation
Therapeutic role of TGF-β-neutralizing antibody in mouse cyclosporin a nephropathy:: Morphologic improvement associated with functional preservation
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DOI：
10.1097/01.asn.0000042168.43665.9b
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发表时间：
2003-02-01
影响因子：
13.6
通讯作者：
Ledbetter, S
中科院分区：
文献类型：
--
作者：
Ling, H;Li, XM;Ledbetter, S
TGF-β被认为在环孢菌素A（CsA）诱导的肾病的发展中起核心作用。本研究研究了1D 11（一种鼠泛特异性TGF-β中和单克隆抗体）在慢性CsA肾病ICR小鼠模型中的作用。小鼠给予低盐饮食（0.01%钠）1周，然后给予CsA治疗（30 mg/kg，皮下注射，每日一次）4周。在CsA给药终止后立即开始给予1D 11（2.5 mg/kg，腹腔内，3次/周），并持续至8周。CsA引起广泛的肾脏组织病理学改变，包括肾小管损伤、间质浸润和纤维化、III型胶原沉积和肾小管上皮细胞凋亡。1D 11改善CsA诱导的组织病理学改变，显著减少III型胶原的表达和沉积。此外，编码TGF-β 1和TGF-β 2的mRNA水平升高显著降低。1D 11对肾小管上皮细胞凋亡的保护率为48%（P < 0.05）。相反，13 C4（对照抗体）对上述任何终点均无显著影响。重要的是，1D 11对CsA诱导的形态学改变的影响之后，与用13 C4处理的CsA小鼠相比，在处理8周后血清肌酐水平降低（13 C4，0.45 +/- 0.09; 1D 11，0.30 +/- 0.08; P < 0.05）。内皮型一氧化氮合酶（eNOS），诱导型一氧化氮合酶（iNOS），硝基酪氨酸，和组织缺氧进行了检查，使用特异性抗体的免疫染色。在CsA处理的小鼠肾脏的小动脉内皮中eNOS显著减少，而在皮质小管中诱导iNOS。小动脉和肾小管中均发现组织缺氧，而硝基酪氨酸则定位于肾小管中。给予1D 11改善组织缺氧并减少硝基酪氨酸形成。此外，iNOS和eNOS表达的相互变化通过1D 11正常化。本研究表明，在现有慢性CsA肾病的背景下，1D 11给药改善了形态学改变并保留了肾功能。
TGF-beta is believed to play a central role in the development of Cyclosporin A (CsA)-induced nephropathy. This study investigated the effects of 1D11, a murine pan-specific TGF-beta-neutralizing monoclonal antibody, in an ICR mouse model of chronic CsA nephropathy. Mice were administered a low-salt diet (0.01% sodium) for 1 wk followed by CsA treatment (30 mg/kg, subcutaneously, daily) for 4 wk. 1D11 was administered (2.5 mg/kg, intraperitoneally, 3 times/ wk) beginning immediately after the termination of CsA dosing and continued through 8 wk. CsA caused extensive renal histopathologic alterations, including tubular damage, interstitial infiltrates and fibrosis, deposition of collagen III, and apoptosis of tubular epithelial cells. 1D11 ameliorated the CsA-induced histopathologic alterations, with significant reduction in collagen III expression and deposition. Additionally, elevated levels of mRNA encoding TGF-beta1 and TGF-beta2 were significantly reduced. 1D11 also protected tubular epithelial cells from apoptosis by 48% (P < 0.05). In contrast, 13C4 (a control antibody) had no significant effect on any of the end-points described above. Importantly, the effects of 1D11 on the CsA-induced morphologic alterations were followed by a reduction in serum creatinine level when compared with CsA mice treated with 13C4 (13C4, 0.45 +/- 0.09; 1D11, 0.30 +/- 0.08; P < 0.05) after 8 wk of treatment. Endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), nitrotyrosine, and tissue hypoxia were examined by immunostaining using specific antibodies. eNOS was significantly reduced in the endothelium of arterioles in the kidneys of mice treated with CsA, whereas iNOS was induced in the cortical tubules. Tissue hypoxia was found in both the arterioles and tubules, whereas nitrotyrosine was localized in the tubules. Administration of 1D11 improved tissue hypoxia and reduced nitrotyrosine formation. Moreover, the reciprocal changes in iNOS and eNOS expression were normalized by 1D11. This study demonstrates that 1D11 administration ameliorated morphologic alterations and preserved renal function in the context of existing chronic CsA nephropathy.