Role of epithelial CD74 in renal diseases

上皮CD74在肾脏疾病中的作用

• 批准号: 432698239
• 负责人: Professor Dr. Peter Boor, Ph.D.
• 金额: --
• 依托单位: Institut für Pathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432698239?language=en
• 关键词: Role; epithelial; CD74; renal; diseases

CD74 (MHC class II invariant chain) is involved in antigen presentation, and has been identified as one of the receptors for the cytokine macrophage migration inhibitory factor (MIF). We recently showed that MIF and CD74 mediated the cross-talk between glomerular cells and drive their pathological proliferation in glomerulonephritis. In contrast, we also discovered that MIF can improve tubular cell regeneration, limit cell-cycle arrest and programmed cell death, thereby improving the course of both acute and chronic, non-immune, tubulointerstitial diseases. Our unpublished preliminary data suggest that in these tubulointerstitial diseases, CD74 is expressed de novo in renal tubular cells and that CD74 deficient mice display increased renal fibrosis and inflammation. Here we hypothesize, that CD74 has potent, cytoprotective, non-inflammatory functions that might limit progression of renal diseases. To test our hypothesis we will analyze: i) the expression of CD74 and its co-receptors in different human renal biopsies and experimental animal models focusing on its potential applicability as a kidney disease biomarker; ii) the functional consequences of CD74 neutralization in murine disease models with tubular cell injury; iii) the dependence of CD74 effects on MIF and the potential therapeutic effectiveness of specific CD74 agonists; iv) the molecular mechanisms responsible for the renoprotective effects of CD74, including cell culture experiments and unbiased omic analyses. Collectively, these experiments aim at defining a novel renoprotective molecular pathway mediated by non-inflammatory actions of CD74 in renal diseases.

CD 74（MHC II类不变链）参与抗原呈递，并且已被鉴定为细胞因子巨噬细胞移动抑制因子（MIF）的受体之一。我们最近发现，在肾小球肾炎中，MIF和CD 74介导肾小球细胞之间的相互作用并驱动其病理增殖。相反，我们还发现MIF可以改善肾小管细胞再生，限制细胞周期停滞和程序性细胞死亡，从而改善急性和慢性非免疫性肾小管间质疾病的病程。我们未发表的初步数据表明，在这些肾小管间质疾病中，CD 74在肾小管细胞中重新表达，CD 74缺陷小鼠显示肾纤维化和炎症增加。在这里，我们假设，CD 74具有有效的，细胞保护性的，非炎症性的功能，可能会限制肾脏疾病的进展。为了检验我们的假设，我们将分析：i）CD 74及其共受体在不同的人肾活检和实验动物模型中的表达，重点是其作为肾脏疾病生物标志物的潜在适用性; ii）在具有肾小管细胞损伤的鼠疾病模型中CD 74中和的功能后果; iii）CD 74效应对MIF的依赖性和特异性CD 74激动剂的潜在治疗效果; iv）负责CD 74的肾保护作用的分子机制，包括细胞培养实验和无偏组学分析。总的来说，这些实验旨在定义一种新的肾脏保护分子途径介导的非炎症作用的CD 74在肾脏疾病。