Axl 调控的生存/增殖网络及其在肾小球肾炎小鼠模型中的治疗干预。
Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis.
机构信息
Division of Immunology, Allergy and Rheumatology, Department of Internal Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.
Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, OH, 45267, USA.
出版信息
Arthritis Res Ther. 2022 Dec 28;24(1):284. doi: 10.1186/s13075-022-02965-w.
BACKGROUND
Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). LN pathogenesis is not fully understood. Axl receptor tyrosine kinase is upregulated and contributes to the pathogenic progress in LN. We have reported that Axl disruption attenuates nephritis development in mice.
METHODS
In this study, we analyzed the gene expression profiles with RNA-seq using renal cortical samples from nephritic mice. Axl-KO mice were bred onto a B6.lpr spontaneous lupus background, and renal disease development was followed and compared to the Axl-sufficient B6.lpr mice. Finally, anti-glomerular basement membrane (anti-GBM) Ab-induced nephritic mice were treated with Axl small molecule inhibitor, R428, at different stages of nephritis development. Blood urine nitrogen levels and renal pathologies were evaluated.
RESULTS
Transcriptome analysis revealed that renal Axl activation contributed to cell proliferation, survival, and motility through regulation of the Akt, c-Jun, and actin pathways. Spontaneous lupus-prone B6.lpr mice with Axl deficiency showed significantly reduced kidney damages and decreased T cell infiltration compared to the renal damage and T cell infiltration in Axl-sufficient B6.lpr mice. The improved kidney function was independent of autoAb production. Moreover, R428 significantly reduced anti-GBM glomerulonephritis at different stages of GN development compared to the untreated nephritic control mice. R428 administration reduced inflammatory cytokine (IL-6) production, T cell infiltration, and nephritis disease activity.
CONCLUSIONS
Results from this study emphasize the important role of Axl signaling in LN and highlight Axl as an attractive target in LN.
背景
狼疮肾炎（LN）是系统性红斑狼疮（SLE）最常见和最严重的并发症。LN 的发病机制尚未完全阐明。Axl 受体酪氨酸激酶上调并有助于 LN 的发病进展。我们已经报道 Axl 缺失可减轻狼疮肾炎小鼠的肾炎发展。
方法
在这项研究中，我们使用肾炎小鼠的肾皮质样本进行了 RNA-seq 基因表达谱分析。Axl-KO 小鼠被繁殖到 B6.lpr 自发性狼疮背景下，随后对其进行了肾脏疾病发展的随访，并与 Axl 充足的 B6.lpr 小鼠进行了比较。最后，用 Axl 小分子抑制剂 R428 在肾炎发展的不同阶段治疗抗肾小球基底膜（anti-GBM）Ab 诱导的肾炎小鼠。评估了血尿氮水平和肾脏病理。
结果
转录组分析表明，肾脏 Axl 的激活通过调节 Akt、c-Jun 和肌动蛋白途径促进细胞增殖、存活和迁移。与 Axl 充足的 B6.lpr 小鼠相比，缺乏 Axl 的自发性狼疮倾向的 B6.lpr 小鼠的肾脏损伤和 T 细胞浸润明显减少。改善的肾功能与自身抗体产生无关。此外，与未经治疗的肾炎对照小鼠相比，R428 在不同阶段的 GN 发展中显著降低了抗-GBM 肾小球肾炎。R428 给药减少了炎症细胞因子（IL-6）的产生、T 细胞浸润和肾炎疾病活动。
结论
本研究结果强调了 Axl 信号在 LN 中的重要作用，并突出了 Axl 作为 LN 一个有吸引力的靶点。
Zotero 插件