Department of Biomedicine, University of Bergen, Bergen, Norway.
BerGenBio ASA, Bergen, Norway.
Front Immunol. 2024 Nov 4;15:1446672. doi: 10.3389/fimmu.2024.1446672. eCollection 2024.
The incidence of chronic kidney disease (CKD) is increasing, in parallel with risk factors including obesity and diabetes mellitus. AXL plays a central role in CKD, providing a rationale to evaluate clinical AXL targeting agents.
To determine the efficacy and underlying molecular mechanisms of AXL inhibition in CKD, we employed a murine unilateral ureteral obstruction (UUO) model preventively treated with a selective AXL kinase inhibitor (bemcentinib) during disease progression. We isolated kidneys at an early (3 days) or late (15 days) timepoint and profiled the cell populations using mass cytometry.
Preventive treatment with bemcentinib significantly attenuated fibrosis in the UUO model. The anti-fibrotic effect correlated with a decrease in mesangial cells and inhibition of innate immune cell infiltration, while the proportion of epithelial cells increased. We mapped AXL expression to a unique network of cells in the kidney: mesangial cells, pericytes, macrophages and dendritic cells.
We propose that AXL targeting affects an important cellular interaction network underlying fibrotic progression. These results support the clinical application of AXL targeting agents to treat CKD.
随着肥胖和糖尿病等危险因素的增加，慢性肾脏病（CKD）的发病率也在不断上升。AXL 在 CKD 中起着核心作用，为评估临床 AXL 靶向药物提供了依据。
为了确定 AXL 抑制在 CKD 中的疗效和潜在分子机制，我们在单侧输尿管梗阻（UUO）模型中预防性地使用选择性 AXL 激酶抑制剂（bemcentinib）进行治疗，在疾病进展过程中进行治疗。我们在早期（3 天）或晚期（15 天）时间点分离肾脏，并使用质谱细胞术对细胞群体进行分析。
bemcentinib 的预防性治疗显著减轻了 UUO 模型中的纤维化。抗纤维化作用与系膜细胞减少和固有免疫细胞浸润抑制相关，而上皮细胞的比例增加。我们将 AXL 表达映射到肾脏中的一个独特的细胞网络：系膜细胞、周细胞、巨噬细胞和树突状细胞。
我们提出，AXL 靶向作用影响了纤维化进展的重要细胞相互作用网络。这些结果支持了 AXL 靶向药物在治疗 CKD 中的临床应用。
