The role of podocytic and tubular β-catenin in proteinuric kidney disease

足细胞和管状β-连环蛋白在蛋白尿肾病中的作用

• 批准号: 434049866
• 负责人: Dr. Tilman Jobst-Schwan
• 金额: --
• 依托单位: Medizinische Klinik 4 - Nephrologie und Hypertensiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/434049866?language=en
• 关键词: role; podocytic; tubular; catenin; proteinuric

The functional subunit of kidney, the nephron, consists of a filter body called the glomerulus which prevents filtration of high molecular weight proteins from the blood, and the tubule which recycles smaller molecules and water from the primary urine. The podocytes are the epithelial cells of the glomerular kidney filter. Their impairment leads to leakage of the filter with loss of serum proteins into the urine, a state called proteinuria. The respective human disease is called nephrotic syndrome. The established therapy with steroids distinguishes between steroid sensitive and steroid resistant nephrotic syndrome. Although used since decades, the mechanism behind steroid action on podocytes remains unclear to date.Wnt/β-catenin signaling is a biologically highly conserved cellular signal transduction pathway that has important functions in embryogenesis, cell proliferation, cell differentiation and migration. While Wnt/β-catenin was often associated with functional impairment of the kidney and damage of podocytes in the past, recent publications indicate a beneficial role of Wnt/β-catenin signaling in cellular renewal. It has been shown that the Wnt/β-catenin pathway is essential for regeneration and repair of tubular damage in acute kidney injury. In contrast, constant activation of Wnt/β-catenin signaling in chronic kidney disease leads to progression of the disease, so that in this case β-catenin inhibition may have protective effects. Thus, Wnt/β-catenin signaling can have differential influences on kidney diseases dependent on activation time and intensity. Moreover, we have shown previously in podocytes that the location of β-catenin within the cell is important as well, with cell membrane bound β-catenin being protective but nuclear β-catenin causing cellular dedifferentiation and dysfunction of the glomerulus. Recently, we established that loss of the gene MAGI2 in zebrafish causes a type of nephrotic syndrome that reacts paradoxically on steroid treatment with accelerated disease progression upon treatment.With this proposal, we aim to investigate how we can promote the beneficial function of β-catenin in both glomerulus and tubule. Firstly, we will test compounds in a podocyte cell culture model for their ability to strengthen the protective membranous β-catenin localization in podocytes in order to reveal potential novel treatment options in nephrotic syndrome. Secondly, we will employ mouse and zebrafish knock-out models of the gene MAGI2 to better understand the mechanism behind steroid action on podocytes and to ultimately find more specific drugs with less side effects. Lastly, we will use tubular cell culture models and proteinuric mouse models to determine how proteinuria activates β-catenin in the tubule. These insights may help us to establish a second tubular point of action in treatment of nephrotic syndrome. To prove the clinical relevance of these findings, some of them will be confirmed in clinical human specimen.

肾的功能亚单位，肾单位，由称为肾小球的过滤体和小管组成，肾小球防止高分子量蛋白质从血液中过滤，小管从初级尿中过滤较小的分子和水。足细胞是肾小球肾滤过器的上皮细胞。它们的损伤导致过滤器泄漏，血清蛋白损失到尿液中，这种状态称为蛋白尿。相应的人类疾病被称为肾病综合征。已建立的类固醇治疗区分类固醇敏感型和类固醇耐药型肾病综合征。Wnt/β-catenin信号通路是一条生物学上高度保守的细胞信号转导通路，在胚胎发生、细胞增殖、细胞分化和迁移等过程中发挥重要作用。虽然Wnt/β-连环蛋白在过去常常与肾功能损害和足细胞损伤相关，但最近的出版物表明Wnt/β-连环蛋白信号传导在细胞更新中的有益作用。研究表明，Wnt/β-catenin通路对急性肾损伤中肾小管损伤的再生和修复至关重要。相比之下，慢性肾病中Wnt/β-连环蛋白信号传导的持续激活导致疾病进展，因此在这种情况下，β-连环蛋白抑制可能具有保护作用。因此，Wnt/β-连环蛋白信号传导可以对肾脏疾病具有依赖于激活时间和强度的不同影响。此外，我们之前已经在足细胞中表明，β-连环蛋白在细胞内的位置也很重要，细胞膜结合的β-连环蛋白具有保护作用，但核β-连环蛋白导致细胞去分化和肾小球功能障碍。最近，我们确定斑马鱼MAGI 2基因的缺失导致一种肾病综合征，这种肾病综合征对类固醇治疗的反应是矛盾的，治疗后疾病进展加快。通过这一提议，我们的目标是研究如何促进β-连环蛋白在肾小球和肾小管中的有益功能。首先，我们将在足细胞培养模型中测试化合物增强足细胞中保护性膜β-连环蛋白定位的能力，以揭示肾病综合征的潜在新治疗选择。其次，我们将采用MAGI 2基因的小鼠和斑马鱼敲除模型，以更好地了解类固醇对足细胞作用的机制，并最终找到副作用更小的更特异性药物。最后，我们将使用肾小管细胞培养模型和蛋白尿小鼠模型来确定蛋白尿如何激活肾小管中的β-连环蛋白。这些见解可能有助于我们建立治疗肾病综合征的第二个肾小管作用点。为了证明这些发现的临床相关性，其中一些将在临床人体标本中得到证实。