Protection Effect of Exogenous Fibroblast Growth Factor 21 on the Kidney Injury in Vascular Calcification Rats

Abstract

Background:Chronic kidney disease (CKD) is closely related to the cardiovascular events in vascular calcification (VC). However, little has known about the characteristics of kidney injury caused by VC. Fibroblast growth factor 21 (FGF21) is an endocrine factor, which takes part in various metabolic actions with the potential to alleviate metabolic disorder diseases. Even FGF21 has been regarded as a biomarker in CKD, the role of FGF21 in CKD remains unclear. Therefore, in this study, we evaluate the FGF21 on the kidney injury in VC rats.Methods:The male Sprague-Dawley rats were divided into three groups: (1) control group, (2) Vitamin D3 plus nicotine (VDN)-induced VC group, (3) FGF21-treated VDN group. After 4 weeks, the rats were killed and the blood was collected for serum creatinine, urea nitrogen, calcium, and phosphate measurement. Moreover, the renal tissues were homogenized for alkaline phosphatases (ALPs) activity and calcium content. The levels of FGF21 protein were measured by radioimmunoassay. The levels of β-Klotho and FGF receptor 1 (FGFR1) protein were measured by enzyme-linked immunosorbent assay (ELISA). The structural damage and calcifications in aortas were stained by Alizarin-red S. Moreover, the structure of kidney was observed by hematoxylin and eosin staining.Results:The renal function impairment caused by VDN modeling was ameliorated by FGF21 treatment, inhibited the elevated serum creatinine and urea level by 20.5% (34.750 ± 4.334 μmol/L vs. 27.630 ± 2.387 μmol/L) and 4.0% (7.038 ± 0.590 mmol/L vs. 6.763 ± 0.374 mmol/L; P < 0.01), respectively, together with the structural damages of glomerular atrophy and renal interstitial fibrosis. FGF21 treatment downregulated the ALP activity, calcium content in the kidney of VC rats by 42.1% (P < 0.01) and 11.7% (P < 0.05) as well as ameliorated the aortic injury and calcification as compared with VDN treatment alone group, indicating an ameliorative effect on VC. ELISA assays showed that the expression of β-Klotho, a component of FGF21 receptor system, was increased in VDN-treated VC rats by 37.4% (6.588 ± 0.957 pg/mg vs. 9.054 ± 0.963 pg/mg; P < 0.01), indicating an FGF21-resistant state. Moreover, FGF21 treatment downregulated the level of β-Klotho in renal tissue by 16.7% (9.054 ± 0.963 pg/mg vs. 7.544 ± 1.362 pg/mg; P < 0.05). However, the level of FGFR1, the receptor of FGF21, kept unchanged under VDN and VDN plus FGF21 administration (0.191 ± 0.0376 ng/mg vs. 0.189 ± 0.032 ng/mg vs. 0.181 ± 0.034 ng/mg; P > 0.05).Conclusions:In the present study, FGF21 was observed to ameliorate the kidney injury in VDN-induced VC rats. FGF21 might be a potential therapeutic factor in CKD by cutting off the vicious circle between VC and kidney injury.

Research Progress of Fibroblast Growth Factor 21 in Fibrotic Diseases

“…After 3-month FGF21 treatment, severe renal dysfunction, morphological changes, inflammation, apoptosis, and fibrosis observed in OVE26 mice were significantly attenuated, indicating, for the first time, that FGF21 induces a therapeutic effect on diabetic nephropathy in OVE26 mice [ 165 ]. A similar phenomenon was observed in renal fibrosis and chronic renal impairment due to vascular calcification [ 168 ]. The latest research shows that FGF21 benefits CKD by cutting off the vicious circle between VC and kidney injury [ 168 ].…”

Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT

“…Increasing clinical studies have demonstrated that circulating FGF21 levels are dramatically increased in patients with various kidney diseases, including chronic kidney disease (CKD) [23,24], kidney transplantation [25,26], ESRD [27], early-stage diabetic kidney disease [28], acute renal dysfunction [29], and long-term peritoneal dialysis [30], indicating that an increase in FGF21 levels above baseline is a stress response to induce renal protection. This hypothesis was confirmed by a subsequent study, which showed that the administration of FGF21 maintained renal function in mice with CKD [31]. Kim et al [32] reported that FGF21 improved insulin resistance and ameliorated renal injury in spontaneous type 2 diabetes mellitus (db/db) mice.…”

Possible effects of fibroblast growth factor 21 on vascular calcification via suppressing activating transcription factor 4 mediated apoptosis and osteogenic transformation in rats

“…The study was approved by the Institutional Animal Care and Use Committee of Capital Medical University. The experimental procedures and protocols performed in this study were in concordance with the ethical approval of Animals' Model Research Committee of the Capital Medical University 13 …”

“…The experimental procedures and protocols performed in this study were in concordance with the ethical approval of Animals' Model Research Committee of the Capital Medical University. 13 Antibodies against p-PERK and PERK were from Cell Signaling Technology. Antibodies against caspase-3, GAPDH, and all secondary antibodies were from Santa Cruz Biotechnology.…”