Role of epithelial CD74 in renal diseases

CD74 （MHC II类不变性链）参与抗原递呈，并已被确定为细胞因子巨噬细胞迁移抑制因子（MIF）的受体之一。我们最近发现，在肾小球肾炎中，MIF和CD74介导肾小球细胞间的串扰并驱动其病理增殖。相反，我们还发现MIF可以促进小管细胞再生，限制细胞周期阻滞和程序性细胞死亡，从而改善急性和慢性非免疫性小管间质疾病的病程。我们未发表的初步数据表明，在这些小管间质疾病中，CD74在肾小管细胞中重新表达，CD74缺陷小鼠表现出肾脏纤维化和炎症增加。在这里，我们假设CD74具有有效的细胞保护和非炎症功能，可能会限制肾脏疾病的进展。为了验证我们的假设，我们将分析：i) CD74及其共受体在不同人类肾脏活检和实验动物模型中的表达，重点关注其作为肾脏疾病生物标志物的潜在适用性；ii) CD74中和对小管细胞损伤小鼠疾病模型的功能影响；iii) CD74效应对MIF的依赖性以及特异性CD74激动剂的潜在治疗效果；iv) CD74对肾保护作用的分子机制，包括细胞培养实验和无偏倚组学分析。总的来说，这些实验旨在定义一种由CD74在肾脏疾病中的非炎症作用介导的新的肾保护分子途径。

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 Our unpublished preliminary data suggest that in these tubulointerstitial diseases, CD74 is expressed de novo in renal tubular cells and that CD74 deficient mice display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.