Renal cell-expressed TNF receptor 2, not receptor 1, is essential for the development of glomerulonephritis.
Renal cell-expressed TNF receptor 2, not receptor 1, is essential for the development of glomerulonephritis.
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DOI：
10.1172/jci23348
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发表时间：
2005-05
期刊：
影响因子：
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通讯作者：
V. Vielhauer;G. Stavrakis;T. Mayadas
中科院分区：
文献类型：
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作者：
V. Vielhauer;G. Stavrakis;T. Mayadas
TNF对于肾小球肾炎的发展至关重要，肾小球肾炎是一种免疫介导的疾病，是世界范围内肾衰竭的主要原因。然而，TNF具有促炎和免疫抑制特性，可能在2种TNF受体（TNFRs）， TNFR1和TNFR2水平上分离。tnfr1缺陷小鼠遭受免疫复合物介导的肾小球肾炎后，在疾病诱导后的早期时间点，蛋白尿和肾小球损伤较少，肾白细胞浸润较少，这与肾毒性兔IgG的全身免疫应答降低有关。然而，在较晚的时间点，蛋白尿和肾脏病理与野生型对照相似，TNFR1的缺乏导致肾T细胞过度积聚，并导致这些细胞的凋亡减少。与之形成鲜明对比的是，尽管存在完整的全身免疫反应，但tnfr2缺陷小鼠在所有时间点都完全免受肾小球肾炎的侵害。研究人员在肾小球内皮细胞上诱导TNFR2，发现TNFR2在肾小球肾炎和肾小球补体沉积中表达是必需的，而非白细胞。因此，TNFR1促进全身免疫反应和肾T细胞死亡，而内在细胞TNFR2在补体依赖性组织损伤中起关键作用。因此，特异性阻断TNFR2可能是治疗免疫介导的肾小球肾炎的一种有前景的策略。
TNF is essential for the development of glomerulonephritis, an immune-mediated disorder that is a major cause of renal failure worldwide. However, TNF has proinflammatory and immunosuppressive properties that may segregate at the level of the 2 TNF receptors (TNFRs), TNFR1 and TNFR2. TNFR1-deficient mice subjected to immune complex-mediated glomerulonephritis developed less proteinuria and glomerular injury, and fewer renal leukocyte infiltrates at early time points after disease induction, and this was associated with a reduced systemic immune response to nephrotoxic rabbit IgG. However, proteinuria and renal pathology were similar to those in wild-type controls at later time points, when lack of TNFR1 resulted in excessive renal T cell accumulation and an associated reduction in apoptosis of these cells. In sharp contrast, TNFR2-deficient mice were completely protected from glomerulonephritis at all time points, despite an intact systemic immune response. TNFR2 was induced on glomerular endothelial cells of nephritic kidneys, and TNFR2 expression on intrinsic cells, but not leukocytes, was essential for glomerulonephritis and glomerular complement deposition. Thus, TNFR1 promotes systemic immune responses and renal T cell death, while intrinsic cell TNFR2 plays a critical role in complement-dependent tissue injury. Therefore, therapeutic blockade specifically of TNFR2 may be a promising strategy in the treatment of immune-mediated glomerulonephritis.