Drug Design, Development and Therapy (Feb 2020)
AZD4547 Attenuates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting Inflammation: The Role of FGFR1 in Renal Tubular Epithelial Cells
Abstract
Xuemei Chen,1,* Xuejiao Zhang,1,* Jiajun Xu,2 Yiqing Zhao,1 Jiachun Bao,1 Zhanxiong Zheng,2 Jibo Han2 1Department of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214041, People’s Republic of China; 2Department of Cardiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jibo HanDepartment of Cardiology, The Second Affiliated Hospital of Jiaxing University, Huancheng North Road 1518, Jiaxing, Zhejiang 314000, People’s Republic of ChinaTel +86-152 5863 9207Email [email protected]: Inflammation plays an important role in the pathogenesis of acute kidney injury (AKI). Fibroblast growth factor receptor 1 (FGFR1) signaling is implicated in kidney pathology. AZD4547 is a small molecule inhibitor of FGFR1.Materials and Methods: Here, we investigated whether AZD4547 could mitigate inflammatory responses in AKI. C57BL/6 mice were injected with lipopolysaccharide (LPS) to induce AKI. FGFR1 was blocked using AZD4547 or CRISPR/Cas9 genome editing. After immunofluorescent double-staining of kidney tissues showing that P-FGFR1 was localized to renal tubular epithelial cells, a tubular epithelial cell line (NRK-52E) was used for in vitro analysis.Results: AZD4547 significantly reduced renal inflammation, cell apoptosis, and kidney dysfunction in AKI mice. In vitro, treatment of NRK-52E cells with AZD4547 attenuated LPS-induced inflammatory responses and was associated with downregulated P-FGFR1 levels. These findings were further confirmed in NRK-52E cells by knocking down the expression of FGFR1.Conclusion: Our findings provide direct evidence that FGFR1 mediates LPS-induced inflammation leading to renal dysfunction. We also show that AZD4547 is a potential therapeutic agent to reduce inflammatory responses in AKI. Both FGFR1 and AZD4547 may interesting therapeutic options to combat AKI.Keywords: acute kidney injury, lipopolysaccharide, inflammation, AZD4547, renal tubular epithelial cells
