Zhuo Xu1, Xingwen Zhu2, Mingjie Wang1, Yibing Lu2, Chunsun Dai1. 1. Center for Kidney Disease, the Second Affiliated Hospital, Nanjing Medical University, Nanjing, China. 2. Endocrine Department, the Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Abstract
BACKGROUND: Fibroblast growth factors (FGFs) are heparin-binding proteins involved in a variety of biological processes, and part of them may act through binding with cell membrane receptor FGFR2. OBJECTIVES: To clarify the role and mechanisms of FGFR2 signaling in tubular cell survival and acute kidney injury (AKI). METHOD: In this study, kidney ischemia/reperfusion (IR) or cisplatin injection was used to induce AKI in mice. RESULTS: In the kidneys after IR or cisplatin injection, the expression of FGFs and Erk1/2 phosphorylation were elevated. To investigate the role of FGFs in tubular cell survival and AKI, a mouse model with tubular cell specific FGFR2 gene disruption was generated. The knockouts were born normal. At 2 months of age, about one-third of the knockouts developed mild hydronephrosis. Ablation of FGFR2 in tubular cells aggravated acute kidney dysfunction as well as tubular cell apoptosis induced by IR or cisplatin. In addition, Erk1/2 phosphorylation was less in the knockout kidneys than in control littermates at day 1 after cisplatin injection. In cultured NRK-52E cells, recombinant FGF2 protein induced Erk1/2 phosphorylation and inhibited cisplatin-induced cell death. PD98059 abolished Erk1/2 phosphorylation and partly reversed the protective effect of FGF2 on cisplatin-induced cell death. CONCLUSIONS: This study indicates that FGF/FGFR2 signaling plays an important role in protecting against tubular cell death and AKI, which is partly through stimulating Erk1/2 activation.
BACKGROUND: Fibroblast growth factors (FGFs) are heparin-binding proteins involved in a variety of biological processes, and part of them may act through binding with cell membrane receptor FGFR2. OBJECTIVES: To clarify the role and mechanisms of FGFR2 signaling in tubular cell survival and acute kidney injury (AKI). METHOD: In this study, kidney ischemia/reperfusion (IR) or cisplatin injection was used to induce AKI in mice. RESULTS: In the kidneys after IR or cisplatin injection, the expression of FGFs and Erk1/2 phosphorylation were elevated. To investigate the role of FGFs in tubular cell survival and AKI, a mouse model with tubular cell specific FGFR2 gene disruption was generated. The knockouts were born normal. At 2 months of age, about one-third of the knockouts developed mild hydronephrosis. Ablation of FGFR2 in tubular cells aggravated acute kidney dysfunction as well as tubular cell apoptosis induced by IR or cisplatin. In addition, Erk1/2 phosphorylation was less in the knockout kidneys than in control littermates at day 1 after cisplatin injection. In cultured NRK-52E cells, recombinant FGF2 protein induced Erk1/2 phosphorylation and inhibited cisplatin-induced cell death. PD98059 abolished Erk1/2 phosphorylation and partly reversed the protective effect of FGF2 on cisplatin-induced cell death. CONCLUSIONS: This study indicates that FGF/FGFR2 signaling plays an important role in protecting against tubular cell death and AKI, which is partly through stimulating Erk1/2 activation.
Authors: Swojani Shrestha; Sonalika Singhal; Matthew Kalonick; Rachel Guyer; Alexis Volkert; Seema Somji; Scott H Garrett; Donald A Sens; Sandeep K Singhal Journal: J Cell Mol Med Date: 2021-10-09 Impact factor: 5.310