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: 10625384
• 负责人: John Cijiang He
• 金额: $ 50.89万
• 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/10625384
• 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; podocyte; postmitotic; prevent; receptor; single nucleus RNA-sequencing; therapeutic target; transcription factor; transcriptome sequencing

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.

迄今为止，估计约有 3000 万美国人患有慢性肾病，这是一种主要疾病 在美国，足细胞是终末分化的有丝分裂后内脏上皮细胞。 肾小球中的细胞，其主要功能是维持肾滤过屏障。 快速进展性肾小球肾炎 (RPGN) 和局灶节段性肾炎亚型等疾病 肾小球硬化症 (FSGS)，特别是塌陷性和细胞性变异，以初始足细胞损伤为特征 和脱离，触发邻近壁上皮细胞（PEC）的异常增殖，导致 先前的研究表明，新月体或假新月体形成以及最终的肾小球硬化。 足细胞和壁上皮细胞（PEC）之间的相互作用可能在这些疾病的发病机制中发挥作用 增生性病变，但信号转导器和激活剂的激活机制仍不清楚。 转录 3 (STAT3) 与 RPGN 和崩溃的启动和进展有关 尽管 STAT3 信号传导的激活在 RPGN 和 FSGS 的发病机制中起着重要作用。 在 FSGS 亚型中，STAT3 信号传导的调节仍有待探索。 锌指转录因子 Krüppel 样因子 4 (KLF4) 可能作为关键的负调节因子 尽管 KLF 家族的几个成员与细胞分化有关， 我们的初步数据表明，KLF4 最初被确定为增殖的关键负调节因子。 小鼠足细胞特异性 Klf4 缺失导致肾小球 STAT3 信号传导失调的激活， 豆荚细胞损伤、PEC 增殖以及最终的 FSGS 和肾衰竭。 STAT3信号的激活与肾活检肾小球中KLF4的表达呈负相关 RPGN 与对照样本的比较 基于这些数据，我们寻找足细胞特异性的 KLF4。 是维持足细胞完整性和预防 PEC 异常增殖所必需的 我们建议通过以下具体目标来检验这一假设：(1) 研究足细胞特异性 KLF4-STAT3 信号在增殖性肾小球病中的必要作用 (2)确定增殖性肾小球病中介导足细胞-PEC串扰的中心机制。 本研究提案旨在通过阐明机制来解决该领域当前的空白 足细胞丢失引发增殖性肾小球病中 PEC 的异常增殖。 我们项目的目的是确定诱导 PEC 增殖的失调途径，这些途径可能作为“药物” 增殖性肾小球病的发生和/或进展的目标。