Different effects of global osteopontin and macrophage osteopontin in glomerular injury.
Different effects of global osteopontin and macrophage osteopontin in glomerular injury.
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DOI：
10.1152/ajprenal.00458.2017
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发表时间：
2018-10
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通讯作者：
Jessica Trostel;L. Truong;Carlos Roncal-Jimenez;M. Miyazaki;Shinobu Miyazaki‐Anzai;M. Kuwabara;Rachel H
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文献类型：
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作者：
Jessica Trostel;L. Truong;Carlos Roncal-Jimenez;M. Miyazaki;Shinobu Miyazaki‐Anzai;M. Kuwabara;Rachel H
骨桥蛋白（OPN）是一种促炎和抗炎分子，同时减弱氧化应激。炎症和氧化应激在肾小球肾炎的发病机制和肾损伤的进展中起作用。重要的是，OPN在肾炎肾中高度诱导。为了进一步表征OPN在肾损伤中的作用，我们在抗肾小球基底膜反应性血清诱导的免疫（NTS）肾炎（一种炎症性和进行性肾脏疾病模型）中使用OPN-/-小鼠。正常野生型（WT）和OPN-/-小鼠未显示组织学差异。然而，与WT小鼠相比，OPN-/-小鼠的肾炎肾显示出严重的损伤。肾小球增生、坏死性病变、新月体形成和肾小管间质损伤在OPN-/-小鼠中显著更高。OPN-/-小鼠肾小球和肾小球中巨噬细胞浸润增加，IL-6、CCL 2和趋化因子CXCL 1表达增加。此外，OPN-/-小鼠肾脏中胶原（Col）I、Col III和Col IV沉积增加。在OPN-/-小鼠的肾炎肾脏中观察到活性氧生成酶Nox 4的表达升高和Nrf 2（一种抑制活性氧和炎症通路的分子）的表达减弱。值得注意的是，与接受WT巨噬细胞的小鼠相比，选择性耗尽巨噬细胞并用OPN-/-巨噬细胞重建的NTS肾炎的CD 11b白喉毒素受体小鼠显示出更少的肾损伤。这些发现表明，在全局OPN-/-小鼠中，炎症和氧化还原失衡增加，介导肾损伤。然而，巨噬细胞OPN的缺乏是保护性的，表明巨噬细胞OPN在NTS肾炎的肾损伤的诱导和进展中起作用。
Osteopontin (OPN) is a pro-and anti-inflammatory molecule that simultaneously attenuates oxidative stress. Both inflammation and oxidative stress play a role in the pathogenesis of glomerulonephritis and in the progression of kidney injury. Importantly, OPN is highly induced in nephritic kidneys. To characterize further the role of OPN in kidney injury we used OPN-/- mice in antiglomerular basement membrane reactive serum-induced immune (NTS) nephritis, an inflammatory and progressive model of kidney disease. Normal wild-type (WT) and OPN-/- mice did not show histological differences. However, nephritic kidneys from OPN-/- mice showed severe damage compared with WT mice. Glomerular proliferation, necrotizing lesions, crescent formation, and tubulointerstitial injury were significantly higher in OPN-/- mice. Macrophage infiltration was increased in the glomeruli and interstitium in OPN-/- mice, with higher expression of IL-6, CCL2, and chemokine CXCL1. In addition, collagen (Col) I, Col III, and Col IV deposition were increased in kidneys from OPN-/- mice. Elevated expression of the reactive oxygen species-generating enzyme Nox4 and blunted expression of Nrf2, a molecule that inhibits reactive oxygen species and inflammatory pathways, was observed in nephritic kidneys from OPN-/- mice. Notably, CD11b diphteria toxin receptor mice with NTS nephritis selectively depleted of macrophages and reconstituted with OPN-/- macrophages showed less kidney injury compared with mice receiving WT macrophages. These findings suggest that in global OPN-/- mice there is increased inflammation and redox imbalance that mediate kidney damage. However, absence of macrophage OPN is protective, indicating that macrophage OPN plays a role in the induction and progression of kidney injury in NTS nephritis.