Department of Nephrology and Transplantation, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; Department of Nephrology, Hospital Universitari Bellvitge, Barcelona, Spain; Department of Clinical Sciences, University of Barcelona, Barcelona, Spain.
Department of Nephrology, Hospital Universitari Bellvitge, Barcelona, Spain; Department of Clinical Sciences, University of Barcelona, Barcelona, Spain.
Kidney Int. 2024 Jul;106(1):67-84. doi: 10.1016/j.kint.2024.02.010. Epub 2024 Feb 28.
Parietal epithelial cells (PECs) are kidney progenitor cells with similarities to a bone marrow stem cell niche. In focal segmental glomerulosclerosis (FSGS) PECs become activated and contribute to extracellular matrix deposition. Colony stimulating factor-1 (CSF-1), a hematopoietic growth factor, acts via its specific receptor, CSF-1R, and has been implicated in several glomerular diseases, although its role on PEC activation is unknown. Here, we found that CSF-1R was upregulated in PECs and podocytes in biopsies from patients with FSGS. Through in vitro studies, PECs were found to constitutively express CSF-1R. Incubation with CSF-1 induced CSF-1R upregulation and significant transcriptional regulation of genes involved in pathways associated with PEC activation. Specifically, CSF-1/CSF-1R activated the ERK1/2 signaling pathway and upregulated CD44 in PECs, while both ERK and CSF-1R inhibitors reduced CD44 expression. Functional studies showed that CSF-1 induced PEC proliferation and migration, while reducing the differentiation of PECs into podocytes. These results were validated in the Adriamycin-induced FSGS experimental mouse model. Importantly, treatment with either the CSF-1R-specific inhibitor GW2580 or Ki20227 provided a robust therapeutic effect. Thus, we provide evidence of the role of the CSF-1/CSF-1R pathway in PEC activation in FSGS, paving the way for future clinical studies investigating the therapeutic effect of CSF-1R inhibitors on patients with FSGS.
壁细胞（PECs）是具有骨髓干细胞龛相似性的肾脏祖细胞。在局灶节段性肾小球硬化症（FSGS）中，PECs 被激活并促进细胞外基质沉积。集落刺激因子-1（CSF-1）是一种造血生长因子，通过其特异性受体 CSF-1R 发挥作用，并与几种肾小球疾病有关，尽管其在 PEC 激活中的作用尚不清楚。在这里，我们发现 CSF-1R 在 FSGS 患者活检中的 PEC 和 podocytes 中上调。通过体外研究，发现 PEC 持续表达 CSF-1R。CSF-1 的孵育诱导 CSF-1R 上调和与 PEC 激活相关途径的基因的显著转录调控。具体而言，CSF-1/CSF-1R 激活了 ERK1/2 信号通路并上调了 PEC 中的 CD44，而 ERK 和 CSF-1R 抑制剂均降低了 CD44 的表达。功能研究表明 CSF-1 诱导 PEC 增殖和迁移，同时减少 PEC 向 podocytes 的分化。这些结果在阿霉素诱导的 FSGS 实验性小鼠模型中得到了验证。重要的是，CSF-1R 特异性抑制剂 GW2580 或 Ki20227 的治疗均提供了强大的治疗效果。因此，我们提供了 CSF-1/CSF-1R 途径在 FSGS 中 PEC 激活中的作用的证据，为未来研究 CSF-1R 抑制剂对 FSGS 患者的治疗效果铺平了道路。
