Study On The Function And Mechanism Of Fibroblast Growth Factor Family In Kidney Diseases

Fibroblast growth factors (FGFs) are heparin-binding proteins involved in a variety of biological processes, including cell proliferation, differentiation, survival and angiogenesis through binding its receptor FGFRs. However, the role and mechanisms of FGFs/FGFRs signaling in tubular cell survival and acute kidney injury (AKI) need further investigation. In this study, kidney ischemia/reperfusion or cisplatin injection was used to induce AKI in mice. In the kidneys with ischemia/reperfusion injury (IRI), the expression of FGFs including FGF2, FGF7, FGF10, FGF12, FGF13, FGF18, and FGF22 were up-regulated. Phosphorylated Erkl,2 was also elevated in the IRI kidneys. To further explore the role of FGF signaling in tubular cell survival and AKI in mice, a mouse model with tubular cell specific FGFR2 gene disruption was generated by using Cre-LoxP system. The knockouts were born normal and no obvious kidney dysfunction was found within four months after birth. Specific deletion of FGFR2 in tubular cells in mice aggravated the tubular cell death as well as AKI induced by IRI or cisplatin. In cultured NRK-52E cells, recombinant FGF2 protein could induce Erk1,2 phosphorylation and inhibit cisplatin-induced cell death. PD98059, a specific MEK 1/2 inhibitor, abolished Erk1,2 phosphorylation and partly reversed the protective effect of FGF2 in ciaplatin-induced cell death. Together, this study indicates that FGF2/FGFR2 signaling plays an important role in protecting against tubular cell death and AKI, which is partly through Erk1,2 signaling activation. About 10 percent of population worldwide is suffered from chronic kidney diseases (CKD). Tubulointerstitial fibrosis is one of the most important histologic features that determine progression in CKD. Activated fibroblasts, which are denoted as myofibroblasts and express a-smooth muscle actin (a-SMA), are key effector cells in fibrotic kidneys. Recently studies have shown that fibroblast growth factor 7 (FGF7), a class of paracrine growth factor, plays a key role in kidney development. However, the roles of FGF7 signal in renal fibrosis and in the activation of kidney fibroblasts are still unknown.In this study, FGF7 is overexpressed in vivo by hydrodynamic-based gene transfer method and then renal fibrosis is established at different time points after ischemia/reperfusion injury (IR/I). Exogenous FGF7 aggravates the renal fibrosis in both Sham and fibrotic kidneys. To further explore the role of FGF signaling in fibroblasts activation and kidney fibrosis in mice, a mouse model with fibroblasts specific FGFR2 gene disruption is generated by using Cre-LoxP system. The knockouts are born normal and no obvious kidney dysfunction was found. Specific deletion of FGFR2 in fibroblasts in mice promotes the activation and proliferation of fibroblasts, while ameliorates renal fibrosis. In cultured NRK-49 cells, upregulation of FGF7 can induce Erk1,2 phosphorylation and promote cell proliferation showed by MTT cell-viability assay.Taken together, these results suggest that FGF7-FGFR2 signaling promotes the proliferation and activation of kidney fibroblasts and contributes to the development of interstitial fibrosis. And this roles is partly via activating the Erk1,2 signal pathway. Renal interstitial fibrosis is a morphological hallmark of chronic renal disease(CKD). Macrophage infiltration is one of the most important features of glomerular and tubulointerstitial disease, and the change of macrophage M1/M2 polarization is accompanied with the process of renal fibrosis. Ciculation FGF23 increases early in the course of CKD. However, the functional role of the FGF23 upregulation on accelerates progression of kidney disease remains largely unknown.In this study, FGF23 is overexpressed in vivo by hydrodynamic-based gene transfer method, then renal fibrosis and glomerulosclerosis is established by single injections of doxorubicin(ADR) via tail veins. RAW264.7 is used to study effects of FGF23 on;, macrophage phenotype in vitro.Exogenous FGF23 aggravates both the renal fibrosis and the degree of glomerulosclerosis in ADR model. Meanwhile, the synthesis of fibronectin (FN) and activation of fibroblasts increase in mice with FGF23 overexpression. FGF23 overexpression can also promote TNF-α, MCP-1 and Rantes mRNA expression and M2 macrophage accumulation in fibrotic kidney. In cultured RAW264.7 cells, FGF23 plasmid transfection can induce macrophage converse to M2 phenotype with IL-4-treated.Taken together, these results suggest that in ADR-induced nephropathy model, FGF23 signaling promotes M2 macrophage accumulation and contributes to the development of interstitial fibrosis.