Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies

增殖性肾小球病中足细胞-壁上皮细胞串扰的介导机制

• 批准号: 10773886
• 负责人: John Cijiang He
• 金额: $ 7.35万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10773886
• 关键词: Actins; Address; American; Attenuated; Binding; Cell Adhesion; Cell Cycle; Cell Cycle Checkpoint; Cell Differentiation process; Cellular Stress; ChIP-seq; Chronic Kidney Failure; Cytoskeleton; Data; Development; Differentiation Antigens; Disease; Epithelial Cell Proliferation; Epithelial Cells; Failure; Family; Feedback; Filtration; Focal and Segmental Glomerulosclerosis; Functional disorder; GKLF protein; Genes; Goals; Healthcare; Human; Hyperplasia; Injury; Injury to Kidney; Kidney; Kidney Failure; Kidney Glomerulus; Kruppel-like transcription factors; Laboratories; Lesion; Ligands; Maintenance; Mediating; Mediator; Mitotic; Modeling; Mouse Strains; Mus; Mutate; Organoids; Paracrine Communication; Parietal; Pathogenesis; Pathway interactions; Play; Predisposition; Prevention; Proliferating; Proteomics; Rapidly Progressive Glomerulonephritis; Receptor Activation; Regulation; Renal glomerular disease; Reporting; Research Proposals; Role; Signal Induction; Signal Transduction; Specimen; Stat3 protein; System; Testing; United States; Variant; Visceral; Zinc Fingers; care burden; cell type; comparison control; differential expression; druggable target; glomerulosclerosis; injured; innovation; kidney biopsy; knock-down; member; migration; mouse model; mutant; novel; paracrine; parent grant; podocyte; postmitotic; prevent; receptor; single nucleus RNA-sequencing; therapeutic target; transcription factor; transcriptome sequencing

Parent Grant Abstract: To date, approximately 30 million Americans are estimated to have chronic kidney disease, a major health care burden in the United States. Podocytes are terminally differentiated post-mitotic visceral epithelial cells in the glomerulus whose major function is the maintenance of the renal filtration barrier. Glomerular diseases such as Rapidly Progressive Glomerulonephritis (RPGN) and subtypes of Focal Segmental Glomerulosclerosis (FSGS), in particular collapsing and cellular variants, are marked by initial podocyte injury and detachment, which triggers aberrant proliferation of neighboring parietal epithelial cell (PEC), resulting in crescent or pseudocrescent formation and eventual glomerulosclerosis. Previous studies suggest the crosstalk between podocytes and parietal epithelial cells (PECs) might play a role in the pathogenesis of these hyperplastic lesions, but the mechanisms remain unclear. Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been implicated in the initiation and progression of both RPGN and collapsing FSGS. Although activation of STAT3 signaling plays an important role in the pathogenesis of RPGN and subtypes of FSGS, the regulation of STAT3 signaling remains to be explored. Recent studies demonstrate that a zinc-finger transcription factor, Krüppel- Like Factor 4 (KLF4), might serve as a key negative regulator of STAT3 signaling. Although several members of the KLF family have been implicated in cell differentiation, KLF4 was first identified as a critical negative regulator of proliferation. Our preliminary data suggests that the podocyte-specific loss of Klf4 in mice renders the activation of dysregulated glomerular STAT3 signaling, podocyte injury, PEC proliferation, and eventual FSGS and renal failure. Furthermore, we showed that the activation of STAT3 signaling inversely correlated with KLF4 expression in the glomeruli of kidney biopsies with RPGN as compared to control specimens. Based on these data, we hypothesize that podocyte-specific KLF4 is required for the maintenance of podocyte integrity and prevention of aberrant PEC proliferation in proliferative glomerulopathies. We propose to test this hypothesis through the following specific aims: (1) Investigate the requisite role of podocyte-specific KLF4-STAT3 signaling in proliferative glomerulopathies and (2) Determine the central mechanisms mediating podocyte-PEC crosstalk in proliferative glomerulopathies. This research proposal aims to address a current gap in the field by elucidating the mechanisms by which podocyte loss triggers aberrant proliferation in the PECs in proliferative glomerulopathies. The long-term goal of our project is to identify dysregulated pathways inducing PEC proliferation that might serve as “druggable” targets in the development and/or progression of proliferative glomerulopathies.

父授予摘要： 迄今为止，据估计大约有3000万美国人患有慢性肾脏疾病，这是一种主要健康状况 在美国的护理燃烧。足细胞是末端分化的有丝分化后内脏上皮细胞 诸如主要功能之类的肾小球疾病是维持肾脏过滤屏障。 作为快速进行性肾小球肾炎（RPGN）和局灶性节段性肾小球硬化的亚型 （FSGS），特别是崩溃和细胞变异，以初始足细胞损伤和脱离为特征，这些损伤和脱离 触发相邻顶上上皮细胞（PEC）的异常增殖，导致新月或伪新闻 形成和最终的肾小球硬化。先前的研究表明，足细胞和 顶叶上皮细胞（PEC）可能在这些增生病变的发病机理中起作用，但是 机制仍然不清楚。转录3（STAT3）的信号换能器和激活因子的激活已经 在RPGN和Collapse FSG的主动性和进展中实施。虽然激活STAT3 信号传导在RPGN和FSG的亚型的发病机理中起重要作用，STAT3的调节 信号仍有待探索。最近的研究表明，锌指转录因子krüppel- 像因子4（KLF4）一样，可能是STAT3信号传导的关键负调节剂。虽然有几个成员 KLF家族已在细胞分化中暗示，KLF4首先被确定为关键负调节剂 增殖。我们的初步数据表明，小鼠中KLF4的Podocyte特异性损失使得 肾小球STAT3信号传导，足细胞损伤，PEC增殖和最终FSG的激活 和肾衰竭。此外，我们表明STAT3信号的激活与KLF4成反比 与对照样本相比，在具有RPGN的肾脏活检的肾小球中表达。基于这些 数据，我们假设podocyte特异性KLF4是维持足细胞完整性和 预防增殖肾小球病中异常PEC增殖。我们建议检验这一假设 通过以下特定目的：（1）研究Podocyte特异性KLF4-STAT3信号的必要作用 在增殖的肾小球病中，（2）确定介导Podocyte-Pec串扰的中心机制 在增殖的肾小球病中。该研究建议旨在通过阐明该领域的当前差距 足细胞损失触发PEC中异常增殖的机制 肾小球病。我们项目的长期目标是确定诱导PEC的失调途径 扩散可能是增殖发展和/或进展的“可药”目标 肾小球病。