Add-on anti-TGF-β antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat
Add-on anti-TGF-β antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat
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DOI：
10.1097/01.asn.0000074238.61967.b7
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发表时间：
2003-07-01
影响因子：
13.6
通讯作者：
Remuzzi, G
中科院分区：
文献类型：
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作者：
Benigni, A;Zoja, C;Remuzzi, G
血管紧张素系统（RAS）抑制剂可有效减缓早期糖尿病肾病的肾脏疾病进展，但在后期阶段提供的保护作用并不完善。由于转化生长因子-β（TGF-β）在糖尿病肾病发病机制中的关键作用，本研究测试了同时中断TGF-β和血管紧张素11对明显肾病的糖尿病大鼠疾病进展的影响。用链脲佐菌素诱发单侧肾切除大鼠糖尿病。糖尿病大鼠从第4个月（当动物具有蛋白尿时）至第8个月接受单独的鼠（ID 11）或人（CAT-192）抗TGF-β单克隆抗体或与赖诺普利、13 C4不相关鼠抗体、盐水或赖诺普利的组合。正常动物作为对照。收缩压升高可通过单药治疗得到控制，联合治疗效果更好。IDII和赖诺普利使蛋白尿保持在数值上低于无关抗体和生理盐水的水平，而CAT-192无效。在赖诺普利基础上加入TGF-β抗体可使蛋白尿正常化。对于肾小球硬化和肾小管损伤，获得了一致的结果，这些结果被联合治疗废除。间质体积扩张和淋巴细胞/巨噬细胞的浸润受到1D 11和赖诺普利的限制，并通过其组合进一步减少。1D 11和赖诺普利可部分抑制肾间质中III型胶原的增加，而两者联合使用可使其正常化。结论：抗TGF-β抗体在慢性血管紧张素转换酶（ACE）抑制的背景下可完全抑制蛋白尿和明显糖尿病肾病的肾损伤，为RAS抑制无效的糖尿病患者提供了一种新的治疗和缓解途径。
Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor-beta (TGF-beta) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-beta and angiotensin 11 on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (I D 11) or human (CAT-192) anti-TGF-beta monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. I D I I and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and saline, while CAT-192 was ineffective. The addition of either TGF-beta antibody to lisinopril normalized proteinuria. Consistent results were obtained for glomerulosclerosis and tubular damage, which were abrogated by the combined therapy. Interstitial volume expansion and infiltration of lymphocytes/macrophages were limited by 1D11 and lisinopril and further reduced by their combination. The increase of type III collagen in the renal interstitium was partially attenuated by 1D11 and lisinopril while normalized by their combination. It is concluded that anti-TGF-beta antibody when added to a background of chronic angiotensin-converting enzyme (ACE) inhibition fully arrests proteinuria and renal injury of overt diabetic nephropathy, providing a novel route to therapy and remission of disease for diabetic patients who do not respond to RAS inhibition.