Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies

到目前为止，估计大约有3000万美国人患有慢性肾脏疾病，这是一种主要的 美国的医疗保健负担。足细胞是终末分化的有丝分裂后内脏上皮 肾小球中的细胞，其主要功能是维持肾滤过屏障。肾小球 快速进行性肾小球肾炎(RPGN)和局灶节段亚型等疾病 肾小球硬化(FSGS)，特别是崩塌和细胞变异，最初的足细胞损伤是其特征。 和脱离，触发邻近的壁上皮细胞(PEC)的异常增殖，导致 新月体或假新月的形成和最终的肾小球硬化。此前的研究表明，相声 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起一定作用。 增生性病变，但机制尚不清楚。信号转导和激活器的激活 转录因子3(STAT3)参与了RPGN和塌陷的发生和发展 FSGS。尽管STAT3信号的激活在RPGN和RPGN的发病机制中起着重要作用 对于FSGS的亚型，STAT3信号的调控仍有待探索。最近的研究表明， 锌指转录因子Krüppel样因子4(KLF4)可能是一种关键的负调控因子 STAT3信令。尽管KLF家族的几个成员与细胞分化有关， KLF4最初被认为是一种重要的增殖负性调节因子。我们的初步数据显示 小鼠足细胞特异性KLF4的丢失导致肾小球STAT3信号失控激活， 足细胞损伤、PEC增殖，最终导致FSGS和肾功能衰竭。此外，我们还证明了 肾活检肾小球中STAT3信号的激活与KLF4的表达呈负相关 RPGN与对照标本比较。基于这些数据，我们假设足细胞特异的KLF4 是维持足细胞完整性和防止PEC异常增殖所必需的 增生性肾小球疾病。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疾病中的必要作用 (2)探讨增殖性肾小球疾病中足细胞-PEC串扰的中枢机制。 这项研究提案旨在通过阐明以下机制来解决目前该领域的空白： 在增生性肾小球疾病中，足细胞丢失会触发PECs的异常增殖。长期目标 我们项目的重点是找出诱导PEC增殖的失调通路，这些通路可能是“可用药的” 增生性肾小球疾病发展和/或进展的靶点。

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.