Protection Effect of Exogenous Fibroblast Growth Factor 21 on the Kidney Injury in Vascular Calcification Rats / 中华医学杂志(英文版)

<p><b>Background</b>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.</p><p><b>Methods</b>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.</p><p><b>Results</b>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).</p><p><b>Conclusions</b>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.</p>

Expression of Fibroblast Growth Factor 21 and β-Klotho Regulates Hepatic Fibrosis through the Nuclear Factor-κB and c-Jun N-Terminal Kinase Pathways

BACKGROUND/AIMS: Fibroblast growth factor (FGF) 21 is associated with hepatic inflammation and fibrosis. However, little is known regarding the effects of inflammation and fibrosis on the β-Klotho and FGF21 pathway in the liver. METHODS: Enrolled patients had biopsy-confirmed viral or alcoholic hepatitis. FGF19, FGF21 and β-Klotho levels were evaluated using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blotting. Furthermore, we explored the underlying mechanisms for this process by evaluating nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathway involvement in Huh-7 cells. RESULTS: We observed that the FGF19 and FGF21 serum and mRNA levels in the biopsied liver tissue gradually increased and were correlated with fibrosis stage. Inflammatory markers (interleukin 1β [IL-1β], IL-6, and tumor necrosis factor-α) were positively correlated, while β-Klotho expression was negatively correlated with the degree of fibrosis. In Huh-7 cells, IL-1β increased FGF21 levels and decreased β-Klotho levels. NF-κB and JNK inhibitors abolished the effect of IL-1β on both FGF21 and β-Klotho expression. FGF21 protected IL-1β-induced growth retardation in Huh-7 cells. CONCLUSIONS: These results indicate that the inflammatory response during fibrogenesis increases FGF21 levels and suppresses β-Klotho via the NF-κB and JNK pathway. In addition, FGF21 likely protects hepatocytes from hepatic inflammation and fibrosis.

Expressions of Kidney β-Klotho and Fibroblast Growth Factor Receptor 1 in Experimental Rats Model With Vascular Calcification / 中国循环杂志

Objective: To observe the impact of vascular calcification on kidney injury rats with the expressions of β-Klotho, fibroblast growth factor receptor 1 (FGFR1) in kidney tissue in order to find the predictor for early chronic kidney disease (CKD), to provide the prevention and investigation basis of vascular calcification and CKD. Methods: Vascular calcification model was induced by vitamin D3 and nicotine injection in experimental rats and the animals were divided into 2 groups: Normal control group and Calcification group. n=6 in each group. Serum levels of creatinine and urea nitrogen were examined by sarcosine oxidase method and UV-glutamate dehydrogenase method respectively; blood levels of calcium and phosphorus were detected by biochemistry method; kidney tissue alkaline phosphatases (ALP) activity was measured by ALP detection kit, protein expressions of β-Klotho and FGFR1 were assessed by ELISA.Results: Compared with Normal control group, Calcification group showed increased serum levels of creatinine (35.200±4.087) umol/L vs (26.000±5.0990) umol/L and urea nitrogen (6.900±0.623) mmol/L vs (5.400±0.803) mmol/L, both P<0.05; elevated kidney tissue ALP activity (60.510±31.090) U/g vs (26.590±8.664) U/g and β-Klotho protein expression (9.052±1.238) ng/mg vs (6.860±1.036) ng/mg, both P<0.05. Blood levels of calcium, phosphorus and kidney tissue FGFR1 protein content were similar between 2 groups. Conclusion: Large dose vitamin D3 and nicotine injection may induce vascular calcification and early CKD symptom in experimental rats; β-Klotho protein expression was significantly increased suggesting that β-Klotho had been involved in the early regulation of vascular calcification and it could be used for the early diagnosis of CKD at certain point.