Department of Nephrology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China.
Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Cells. 2023 Jan 4;12(2):214. doi: 10.3390/cells12020214.
The infiltration of inflammatory cells during a kidney injury stimulates myofibroblast activation leading to kidney fibrosis. Fibroblast-specific protein 1 (FSP-1) positive cells have been reported as either myofibroblasts or monocytes during tissue fibrosis. The functions of FSP-1 cells that are associated with the development of renal fibrosis and the signaling pathways that regulate FSP-1 cell activation have not been well defined.
In mice with unilateral ureteral obstruction (UUO), we characterized FSP-1 cells and determined the role of the Notch signaling pathway in the activation of bone marrow-derived FSP-1 cells during kidney fibrosis.
In kidneys from mice with UUO, the FSP-1 cells accumulated significantly in the tubulointerstitial area. By using immunostaining and FSP-1 reporter mice, we found that FSP-1 was co-stained with inflammatory cell markers, but not myofibroblast markers. Results from mice with bone marrow transplantations showed that FSP-1 cells in obstructed kidneys represent a bone marrow-derived population of inflammatory cells. In cultured FSP-1 cells, the inhibition of Notch signaling suppressed the activation and cytokine secretion of FSP-1 cells that were induced by LPS but not by IL-4. The specific KO or blockade of Notch signaling in bone marrow-derived FSP-1 cells suppressed UUO-induced ECM deposition, the infiltration of FSP-1 inflammatory cells, and cytokine production. These responses ameliorated myofibroblast accumulation and renal fibrosis in obstructed kidneys.
Our study reveals that most FSP-1 cells in obstructed kidneys are activated macrophages that are derived from bone marrow and that Notch signaling activates the production of M1 cytokines in FSP-1 monocytes/macrophages, which is important for renal inflammation and fibrosis.
肾损伤过程中炎症细胞的浸润会刺激肌成纤维细胞活化，导致肾纤维化。成纤维细胞特异性蛋白 1（FSP-1）阳性细胞在组织纤维化过程中曾被报道为肌成纤维细胞或单核细胞。然而，FSP-1 细胞在肾纤维化发展中的功能以及调节 FSP-1 细胞活化的信号通路尚未得到很好的定义。
在单侧输尿管梗阻（UUO）小鼠模型中，我们对 FSP-1 细胞进行了特征分析，并确定了 Notch 信号通路在肾纤维化过程中骨髓源性 FSP-1 细胞活化中的作用。
在 UUO 小鼠的肾脏中，FSP-1 细胞在肾小管间质区域大量积聚。通过免疫染色和 FSP-1 报告小鼠，我们发现 FSP-1 与炎症细胞标志物共染色，但不与肌成纤维细胞标志物共染色。骨髓移植小鼠的结果表明，梗阻肾脏中的 FSP-1 细胞代表了骨髓来源的炎症细胞群体。在培养的 FSP-1 细胞中，Notch 信号抑制可抑制 LPS 诱导但不抑制 IL-4 诱导的 FSP-1 细胞的活化和细胞因子分泌。在骨髓源性 FSP-1 细胞中特异性敲除或阻断 Notch 信号可抑制 UUO 诱导的 ECM 沉积、FSP-1 炎症细胞浸润和细胞因子产生。这些反应可改善梗阻肾脏中肌成纤维细胞的积聚和肾纤维化。
我们的研究揭示了梗阻肾脏中大多数 FSP-1 细胞是来源于骨髓的活化巨噬细胞，Notch 信号激活 FSP-1 单核细胞/巨噬细胞中 M1 细胞因子的产生，这对于肾脏炎症和纤维化很重要。
