Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are severe inflammatory disorders that often involve focal necrotizing glomerulonephritis (FNGN) and consequent glomerular scarring, interstitial fibrosis, and chronic kidney disease. Robust murine models of scarring in FNGN that may help to further our understanding of deleterious processes are still lacking. Here, we present a murine model of severe FNGN based on combined administration of antibodies against the glomerular basement membrane (GBM) and myeloperoxidase (MPO), and bacterial lipopolysaccharides (LPS), that recapitulates acute injury and was adapted to investigate subsequent glomerular and interstitial scarring. Hematuria without involvement of other organs occurs consistently and rapidly, glomerular necrosis and crescent formation are evident at 12 days, and consequent glomerular and interstitial scarring at 29 days after initial treatment. Using mass-spectrometric proteome analysis, we provide a detailed overview of matrisomal and cellular changes in our model. We observed increased expression of the matrisome including collagens, fibronectin, tenascin-C, in accordance with human AAV as deduced from analysis of gene expression microarrays and tissue staining. Moreover, we observed tissue infiltration by neutrophils, macrophages, T cells and myofibroblasts upon injury. Experimental inhibition of CXCR4 using AMD3100 led to a sustained histological presence of fibrin extravasate, reduced chemokine expression and leukocyte activation, but did not markedly affect ECM composition. Altogether, we demonstrate an adapted FNGN model that enables the study of matrisomal changes both in disease and upon intervention, as exemplified via CXCR4 inhibition.

抗中性粒细胞胞浆抗体 (ANCA) 相关性血管炎 (AAV) 是严重的炎症性疾病，通常涉及局灶性坏死性肾小球肾炎 (FNGN) 和随之而来的肾小球瘢痕形成、间质纤维化和慢性肾脏疾病。FNGN 中可能有助于进一步了解有害过程的强大的小鼠瘢痕模型仍然缺乏。在这里，我们提出了一种严重 FNGN 的小鼠模型，该模型基于联合施用针对肾小球基底膜 (GBM) 和髓过氧化物酶 (MPO) 的抗体以及细菌脂多糖 (LPS)，它概括了急性损伤并适用于研究随后的肾小球和间质疤痕。不累及其他器官的血尿持续且迅速地发生，12天时肾小球坏死和新月体形成明显，初始治疗后 29 天出现肾小球和间质瘢痕。使用质谱蛋白质组分析，我们提供了模型中基质和细胞变化的详细概述。我们观察到基质体的表达增加，包括胶原蛋白、纤连蛋白、生腱蛋白-C，这与人类 AAV 一致，这是从基因表达微阵列和组织染色分析中推断出来的。此外，我们观察到中性粒细胞、巨噬细胞、T 细胞和肌成纤维细胞在损伤后的组织浸润。使用 AMD3100 对 CXCR4 的实验性抑制导致纤维蛋白外渗物的持续组织学存在，降低趋化因子表达和白细胞活化，但没有显着影响 ECM 组成。共，