Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis
Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis
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DOI：
10.1172/jci4876
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发表时间：
1999-01-01
影响因子：
15.9
通讯作者：
Kelley, VR
中科院分区：
文献类型：
--
作者：
Tesch, GH;Schwarting, A;Kelley, VR
肾脏疾病期间肾实质细胞中的单核细胞趋化蛋白-1 (MCP-1) 上调。为了研究 MCP-1 是否会促进肾小管和/或肾小球损伤，我们在 MCP-1 遗传缺陷小鼠中诱导肾毒性血清肾炎 (NSN)。当 MCP-1 完整菌株中的肾小管和肾小球严重受损时（第 7 天），对小鼠进行了分析。在 MCP-1 完整小鼠中，MCP-1 转录物增加了五倍。 MCP-1主要位于皮质小管内(90%)，大多数皮质小管受损，而很少有肾小球细胞表达MCP-1(10%)。相比之下，MCP-1缺陷小鼠的肾小管损伤（组织病理学、细胞凋亡）显着减少（>40%）。 MCP-1 缺陷小鼠无法免受肾小球损伤（组织病理学、蛋白尿、巨噬细胞流入）。与 MCP-1 缺陷小鼠相比，MCP-1 完整小鼠的肾小管附近巨噬细胞积累增加 (70%，P < 0.005)，表明 MCP-1 募集的巨噬细胞会诱导肾小管上皮细胞 (TEC) 损伤。脂多糖激活的骨髓巨噬细胞释放诱导 TEC 死亡的分子，该死亡不依赖于巨噬细胞或 TEC 的 MCP-1 表达。总之，MCP-1 主要由 TEC 而不是肾小球表达，促进 TEC 而不是肾小球损伤，并增加与 TEC 相邻的活化巨噬细胞，从而在 NSN 期间损伤 TEC。因此，我们建议阻断 TEC MCP-1 表达是某些形式肾脏疾病的治疗策略。
Monocyte chemoattractant protein-1 (MCP-1) is upregulated in renal parenchymal cells during kidney disease. To investigate whether MCP-1 promotes tubular and:or glomerular injury, we induced nephrotoxic serum nephritis (NSN) in MCP-1 genetically deficient mice. Mice were analyzed when tubules and glomeruli were severely damaged in the MCP-1-intact strain (day 7). MCP-1 transcripts increased fivefold in MCP-1-intact mice. MCP-1 was predominantly localized within cortical tubules (90%), and most cortical tubules were damaged, whereas few glomerular cells expressed MCP-1 (10%). By comparison, there was a marked reduction (>40%) in tubular injury in MCP-1-deficient mice (histopathology, apoptosis). MCP-1-deficient mice were not protected from glomerular injury (histopathology, proteinuria, macrophage influx). Macrophage accumulation increased adjacent to tubules in MCP-1-intact mice compared with MCP-1-deficient mice (70%, P < 0.005), indicating that macrophages recruited by MCP-1 induce tubular epithelial cell (TEC) damage. Lipopolysaccharide-activated bone marrow macrophages released molecules that induced TEC death that was not dependent on MCP-1 expression by macrophages or TEC. In conclusion, MCP-1 is predominantly expressed by TEC and not glomeruli, promotes TEC and not glomerular damage, and increases activated macrophages adjacent to TEC that damage TEC during NSN. Therefore, we suggest that blockage of TEC MCP-1 expression is a therapeutic strategy for some forms of kidney disease.