Wnt信号调控巨噬细胞亚型与氧化应激诱导肾纤维化的相关性研究

Chronic kidney disease (CKD) is coming to be the public health problem world widely and causes high morbidity and mortality. Regardless of the causes of diabetes, obesity, hypertension or glomerulonephritis, renal fibrosis is the most common terminal phase of various CKD. In the pathogenesis of renal fibrosis, an uncontrolled inflammation, especially the dramatic activation of macrophage has been thought to be the major cause of fibrosis recently. However, the underlying mechanism has not been reported. In the previous study of the applicant, increasing oxidative stress and macrophage activation were found concomitantly in renal fibrosis models. Further studies show oxidative stress could aggravate progression of the disease, promote macrophage proliferation and activate Wnt signaling. These data suggest the potent correlation of Wnt signaling, macrophage activation and oxidative stress-induced renal fibrosis. To this end, in this study, we will adopt the monocyte cell-derived macrophage, oxidative stress-induced renal fibrosis mouse models and macrophage conditional Wnt knockout mice. We will deeply study whether oxidative stress could trigger macrophage activation and differentiation of its subtypes. And we will discuss the potential role of macrophages and its subtypes in renal fibrosis. In addition, we will detect the dependence of Wnt signaling in macrophage activation and differentiation of its subtypes. Furthermore, we will profoundly test the intimate correlation of Wnt-modulated macrophage and oxidative stress-triggered renal fibrosis. This study will add a new aspect of theoretical understanding of pathogenesis of oxidative stress and renal fibrosis. And promisingly we will find a new target to interfere with the occurrence and progression of renal fibrosis and CKD.

肾脏病已成为“全球公众健康问题”，肾纤维化是多种肾脏病的共同归途，但其分子细胞学机制尚未阐明。器官纤维化常始于失控的炎症反应，研究表明巨噬细胞特异参与多个器官纤维化的形成。但调控巨噬细胞参与肾纤维化的信号机制未见报道。申请人的前期研究表明，氧化应激水平在肾纤维化时异常增高，并参与疾病的发生发展；氧化应激诱导小鼠肾组织巨噬细胞大量增殖活化，伴随多种炎症和致纤维化因子表达增加；氧化应激诱导多种Wnt蛋白的活化。提示巨噬细胞在氧化应激诱导的肾纤维化病变中占有重要地位，并可能与Wnt通路调控相关。为明确机制，本项目拟采用单核细胞诱导的巨噬细胞、氧化应激诱导的肾病和基因敲除小鼠模型，深入研究巨噬细胞参与氧化应激诱导的肾纤维化的作用，进一步阐明Wnt信号调控巨噬细胞活化的机制；明确Wnt蛋白调控巨噬细胞亚型在氧化应激诱导的肾纤维化的参与地位，为氧化应激的致病机制提供新的理论依据并发展新的干预途径。

器官纤维化常始于失控的炎症反应，研究表明巨噬细胞特异参与多个器官纤维化的形成。巨噬细胞是炎症反应中的重要参与细胞，但巨噬细胞的调控机制与肾纤维化的相关性罕见报道。在本课题中，我们采用氧化应激动物模型，深入地研究了Wnt蛋白对于巨噬细胞亚型分化的调节作用，并深入研究了其诱导巨噬细胞外泌体分泌进而导致肾小管上皮细胞损伤的机制。我们的研究发现，巨噬细胞激活在肾病早期即明显增加；氧化应激诱导巨噬细胞表达多种Wnt蛋白；Wnt6蛋白是氧化应激诱导巨噬细胞分化的重要因子，大量存在于巨噬细胞的分泌的外泌体中，介导了巨噬细胞-肾小管上皮细胞的相互交流，诱导了肾小管上皮细胞损伤；巨噬细胞活化分化是促进肾纤维化的发生发展的重要介质。我们的研究论证了Wnt/β-catenin 通路参与氧化应激对于巨噬细胞和亚型分化的影响，将为肾脏纤维化的发病机制提供新的理论依据，从而发展新的干预途径。