微小 RNA 和人类表皮生长因子受体 2 在增生性狼疮性肾炎中的作用。
The Role of MicroRNAs and Human Epidermal Growth Factor Receptor 2 in Proliferative Lupus Nephritis.
机构信息
The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Lisbon, Lisbon, Portugal.
The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia.
出版信息
Arthritis Rheumatol. 2015 Sep;67(9):2415-26. doi: 10.1002/art.39219.
OBJECTIVE
To understand the roles of microRNAs (miRNAs) in proliferative lupus nephritis (LN).
METHODS
A high-throughput analysis of the miRNA pattern of the kidneys of LN patients and controls was performed by molecular digital detection. Urinary miRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target gene expression in human mesangial cells was evaluated by arrays and qRT-PCR. Human epidermal growth factor receptor 2 (HER-2) was analyzed by immunohistochemistry in kidney samples from LN patients and in a murine model of lupus. Urinary levels of HER-2, monocyte chemotactic protein 1 (MCP-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured by enzyme-linked immunosorbent assay.
RESULTS
Levels of the miRNAs miR-26a and miR-30b were decreased in the kidneys and urine of LN patients. In vitro these miRNAs controlled mesangial cell proliferation, and their expression was regulated by HER-2. HER-2 was overexpressed in lupus-prone NZM2410 mice and in the kidneys of patients with LN, but not in other mesangioproliferative glomerulonephritides. HER-2 was found to be up-regulated by interferon-α and interferon regulatory factor 1. Urinary HER-2 was increased in LN and reflected disease activity, and its levels correlated with those of 2 other recognized LN biomarkers, MCP-1 and VCAM-1.
CONCLUSION
The kidney miRNA pattern is broadly altered in LN, which contributes to uncontrolled cell proliferation. Levels of the miRNAs miR-26a and miR-30b are decreased in the kidneys and urine of LN patients, and they directly regulate the cell cycle in mesangial cells. The levels of these miRNAs are controlled by HER-2, which is overexpressed in NZM2410 mice and in the kidneys and urine of LN patients. HER-2, miR-26a, and miR-30b are thus potential LN biomarkers, and blocking HER-2 may be a promising new strategy to decrease cell proliferation and damage in this disease.
目的
了解微小 RNA（miRNA）在增生性狼疮肾炎（LN）中的作用。
方法
通过分子数字检测对 LN 患者和对照者肾脏的 miRNA 模式进行高通量分析。通过定量逆转录聚合酶链反应（qRT-PCR）测量尿 miRNA。通过阵列和 qRT-PCR 评估人系膜细胞中的靶基因表达。通过免疫组织化学分析 LN 患者和狼疮小鼠模型中的肾脏样本中的人类表皮生长因子受体 2（HER-2）。通过酶联免疫吸附试验测量尿 HER-2、单核细胞趋化蛋白 1（MCP-1）和血管细胞黏附分子 1（VCAM-1）的水平。
结果
miR-26a 和 miR-30b 的水平在 LN 患者的肾脏和尿液中降低。在体外，这些 miRNA 控制系膜细胞增殖，其表达受 HER-2 调节。HER-2 在狼疮易感 NZM2410 小鼠和 LN 患者的肾脏中过度表达，但不在其他系膜增生性肾小球肾炎中表达。发现干扰素-α和干扰素调节因子 1 上调 HER-2。LN 中尿 HER-2 增加，反映疾病活动度，其水平与其他 2 种公认的 LN 生物标志物 MCP-1 和 VCAM-1 的水平相关。
结论
LN 中肾脏 miRNA 模式广泛改变，导致不受控制的细胞增殖。miR-26a 和 miR-30b 的水平在 LN 患者的肾脏和尿液中降低，它们直接调节系膜细胞中的细胞周期。这些 miRNA 的水平受 HER-2 控制，HER-2 在 NZM2410 小鼠和 LN 患者的肾脏和尿液中过度表达。因此，HER-2、miR-26a 和 miR-30b 是潜在的 LN 生物标志物，阻断 HER-2 可能是减少这种疾病中细胞增殖和损伤的一种有前途的新策略。
Zotero 插件