<p>AZD4547 Attenuates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting Inflammation: The Role of FGFR1 in Renal Tubular Epithelial Cells</p>

Abstract

Introduction: 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.

Ang II (Angiotensin II)–Induced FGFR1 (Fibroblast Growth Factor Receptor 1) Activation in Tubular Epithelial Cells Promotes Hypertensive Kidney Fibrosis and Injury

“…In addition, FGFR inhibition has been found to protect against LPS-induced kidney fibrosis and dysfunction. 14 Thus, the function of FGFR1 in kidney diseases may depend on the cell types and disease types. It would be a worthwhile effort to investigate the activity of FGFR1 in other renal cells in response to Ang II.…”

“…Specifically, the study showed that pharmacological FGFR inhibitor AZD4547 significantly reduced renal inflammation, cell apoptosis, and kidney dysfunction in LPS-challenged mice. 14 Second, transgenic mice with inducible cardiac-specific overexpression of a constitutively active FGFR1 develop cardiac hypertrophy and fibrosis. 15 The exciting possibility that Ang II mediates renal fibrosis in models of hypertensive kidney disease is the focus of the present study.…”

“…13 There are also reports that FGFR inhibition protects against lipopolysaccharide (LPS)-induced kidney dysfunction. 14 This observation is relevant because LPS-mediated kidney injury also involves elaboration of proinflammatory and fibrogenic proteins, similar to the Ang II challenge. Specifically, the study showed that pharmacological FGFR inhibitor AZD4547 significantly reduced renal inflammation, cell apoptosis, and kidney dysfunction in LPS-challenged mice.…”

MicroRNA‑93 inhibits the apoptosis and inflammatory response of tubular epithelial cells via the PTEN/AKT/mTOR pathway in acute kidney injury

“…In the AKI group (n=10), LPS in 200 µl saline was administrated via intraperitoneal (i.p.) injection (10 mg/kg, 0.2 ml/mouse) for 24 h to induce AKI ( 22 ), while an equal volume of saline was given to control mice (n=10). Ethical approval was obtained from the Animal Experimentation Ethics Committee of the School of Medicine, Shanghai Jiao Tong University (approval no.…”

Research progress of endothelial‐mesenchymal transition in diabetic kidney disease

“…However, inhibition of FGFR1 signalling reduces EndMT in ECs. Further, Terzuoli et al 78 found that pharmacological inhibition of FGFR1 by AZD4547 blocked the formation of the FGFR1/TRAF6 complex, hence inhibiting TRAF6/NF‐κB inflammatory signalling and attenuating renal inflammatory injury and renal dysfunction. It has also been reported that diabetic FGFR1 knockout mice have significantly higher EndMT and EMT levels than diabetic control mice 79 …”