Ablation of FGFR2 in Fibroblasts Ameliorates Kidney Fibrosis after Ischemia/Reperfusion Injury in Mice

Abstract

Background: Fibroblast growth factors (FGFs) are heparin-binding proteins involved in a variety of biological processes. However, the role and mechanisms of FGF/FGFR2 signaling in fibroblast activation and kidney fibrosis need further investigation. Methods: In this study, a mouse model with fibroblast-specific FGFR2 gene disruption was generated. The knockouts were born normal and no kidney dysfunction or histological abnormality was found within 2 months after birth. A kidney ischemia/reperfusion injury (IRI) model was created. Results: Kidney fibrosis was developed in the control littermates within 2 and 4 weeks after IRI, while in the knockouts, total collagen deposition, fibronectin, and alpha smooth muscle actin expression were decreased compared to those in the control littermates. In addition, the numbers of Ki-67-positive interstitial cells as well as TUNEL-positive interstitial cells were lower in the knockout kidneys at 4 weeks after IRI. Phosphorylated extracellular regulated protein kinase 1/2 was decreased in the knockout kidneys at 2 and 4 weeks after IRI compared to those in the control littermates. Conclusion: These results suggest that FGF/FGFR2 signaling may promote the proliferation and activation of kidney fibroblasts, which contribute to the development of kidney fibrosis.

Circulating miRNA-181b-5p, miRNA-223-3p, miRNA-210-3p, let 7i-5p, miRNA-21-5p and miRNA-29a-3p in patients with localized scleroderma as potential biomarkers

“…SMAD1 is a protein mediating TGF-b signalling, activated by α-SMA, that was delineated to be elevated in the skin of patients with SSc i liver fibrosis 56 . FGF2 and FGFR2 are profibrogenic factors that may support the proliferation and activation of kidney fibroblasts, which contribute to the development of renal fibrosis 57 . FOXO3 is an important integrator of profibrotic signaling in lung fibrosis and was found to be downregulated in IPF myofibroblasts 58 .…”

Multiplex Bead Array Assay of a Panel of Circulating Cytokines and Growth Factors in Patients with Albuminuric and Non-Albuminuric Diabetic Kidney Disease

“…It was found that bFGF facilitates epithelial-to-mesenchymal transition of tubular epithelial cells [ 55 ]. Mice with fibroblast-specific disruption of the FGFR2 gene demonstrated decreased total collagen deposition, fibronectin, and alpha smooth muscle actin expression in an ischemia-reperfusion model [ 56 , 57 ]. On the other hand, treatment with bFGF alleviated oxidative stress and apoptosis in the kidney in db / db mice [ 58 ].…”

Fibroblast Growth Factors in the Management of Acute Kidney Injury Following Ischemia-Reperfusion

“…FGF2 reduces the expression of renal damage markers such as ED-1 and a-smooth muscle actin and participates in the regeneration process after ischemic acute renal failure (Villanueva et al, 2006). Xu et al revealed the same results upon the ablation of the receptor FGFR2 in fibroblasts (Xu and Dai, 2017). Such genetic manipulation ameliorates kidney fibrosis after IRI in mice.…”

“…Although IRI mainly affects renal tubular cells, IR-induced pathogenic process and its repair involve interactions between interstitial cells, infiltrated inflammatory cells and epithelial cells. Interestingly, a recent study using a mouse model with fibroblastspecific ablation of Fgfr2 gene indicated that FGFR2 expression in fibroblast may contribute to kidney fibrosis after IRI through promoting renal fibroblast activation and proliferation (Xu and Dai, 2017).…”

“…It has been reported that the expression of Fibroblast growth factors (FGFs) and their receptors (FGFRs) are increased in the context of AKI (Wai et al, 2013;Tan et al, 2017). Furthermore, AKI is more severe upon FGFR deficiency or blockade of its signalling (Villanueva et al, 2008;Xu and Dai, 2017). Some studies demonstrated that renal function recovered after administering various medications, including growth factors and cell transplantation (Ichimura et al, 1996;Patel et al, 2012).…”