Feng Liu, Li Wang, Chao Yu, Huan Qin, Lu Fang, Yi Wang, Jun Wang, Binbin Cui, Na Liu, Shougang Zhuang
Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, USA.
Kidney Dis (Basel). 2021 Jan;7(1):34-49. doi: 10.1159/000509670. Epub 2020 Aug 23.
Our recent studies demonstrated that both nintedanib, an FDA-approved quadruple kinase inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, protect against obstructive kidney disease. It remains unknown whether they have a synergistic effect.
In this study, we investigated the effect of combined administration of nintedanib and gefitinib on renal fibrosis in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO).
Combined treatment with nintedanib and gefitinib after UUO resulted in a greater antifibrotic effect compared with their individual application. Mechanistically, administration of nintedanib blocked UUO-induced phosphorylation of multiple kinase receptors associated renal fibrosis, including platelet-derived growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, and Src family kinase, while gefitinib inhibited EGFR phosphorylation. Their combination also exhibited a more pronounced effect in reducing expression of tissue inhibitors of metalloproteinase-2 (TIMP-2), increasing expression of matrix metalloproteinase-2 (MMP-2), and suppressing renal proinflammatory cytokine expression and macrophage infiltration in the injured kidney. Furthermore, simultaneous administration of nintedanib and gefitinib was more potent in inhibiting UUO-induced renal phosphorylation of signal transducer and activator of transcription-3 (STAT3), nuclear factor-κB, and Smad-3 compared with monotherapy. In cultured renal interstitial fibroblasts, cotreatment with these 2 inhibitors also had synergistic effects in abrogating transforming growth factor β1-induced activation of renal fibroblasts and phosphorylation of Akt, STAT3, and Smad3.
Combined application of nintedanib and gefitinib has a synergistic antifibrotic effect in the kidney and may hold translational potential for the treatment of chronic kidney disease.
我们最近的研究表明，已获美国食品药品监督管理局（FDA）批准的四重激酶抑制剂尼达尼布和表皮生长因子受体（EGFR）抑制剂吉非替尼均可预防梗阻性肾病。它们是否具有协同作用尚不清楚。
在本研究中，我们在单侧输尿管梗阻（UUO）诱导的肾纤维化小鼠模型中，研究了尼达尼布和吉非替尼联合给药对肾纤维化的影响。
与单独应用相比，UUO后尼达尼布和吉非替尼联合治疗产生了更大的抗纤维化作用。机制上，尼达尼布给药可阻断UUO诱导的与肾纤维化相关的多种激酶受体的磷酸化，包括血小板衍生生长因子受体、成纤维细胞生长因子受体、血管内皮生长因子受体和Src家族激酶，而吉非替尼抑制EGFR磷酸化。它们的联合应用在降低金属蛋白酶组织抑制剂-2（TIMP-2）表达、增加基质金属蛋白酶-2（MMP-2）表达以及抑制损伤肾脏中的肾促炎细胞因子表达和巨噬细胞浸润方面也表现出更显著的效果。此外，与单药治疗相比，同时给予尼达尼布和吉非替尼在抑制UUO诱导的肾信号转导和转录激活因子-3（STAT3）、核因子-κB和Smad-3磷酸化方面更有效。在培养的肾间质成纤维细胞中，这两种抑制剂共同处理在消除转化生长因子β1诱导的肾成纤维细胞激活以及Akt、STAT3和Smad3磷酸化方面也具有协同作用。
尼达尼布和吉非替尼联合应用在肾脏中具有协同抗纤维化作用，可能对慢性肾脏病的治疗具有转化潜力。
