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Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome.

ABSTRACT: Cardiorenal syndrome (CRS) has a high mortality, but its pathogenesis remains elusive. Fibroblast growth factor 23 (FGF23) is increased in both renal dysfunction and cardiac dysfunction, and FGF receptor 4 (FGFR4) has been identified as a receptor for FGF23. Deficiency of FGF23 causes growth retardation and shortens the lifespan, but it is unclear whether excess FGF23 is detrimental in CRS. This study sought to investigate whether FGF23 plays an important role in CRS-induced renal fibrosis. A mouse model of CRS was created by surgical myocardial infarction for 12 weeks. CRS mice showed a significant increase of circulatory and renal FGF23 protein levels, as well as an upregulation of p-GSK, active-?-catenin, TGF-?, collagen I and vimentin, a downregulation of renal Klotho expression and induction of cardiorenal dysfunction and cardiorenal fibrosis. These changes were enhanced by cardiac overexpression of FGF23 and attenuated by FGF receptor blocker PD173074 or ?-catenin blocker IGC001. In fibroblasts (NRK-49F), expression of FGFR4 rather than Klotho was detected. Recombinant FGF23 upregulated the expression of p-GSK, active-?-catenin, TGF-?, collagen I and vimentin proteins. These changes were attenuated by FGFR4 blockade with BLU9931 or ?-catenin blockade with IGC001. We concluded that FGF23 promotes CRS-induced renal fibrosis mediated by partly activating FGFR4/?-catenin signaling pathway.

SUBMITTER: Hao H

PROVIDER: S-EPMC7880350 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome.

Hao Huixin H Ma Siyuan S Zheng Cankun C Wang Qiancheng Q Lin Hairuo H Chen Zhenhuan Z Xie Jiahe J Chen Lin L Chen Kaitong K Wang Yuegang Y Huang Xiaobo X Cao Shiping S Liao Wangjun W Bin Jianping J Liao Yulin Y

Aging 20210115 2

Cardiorenal syndrome (CRS) has a high mortality, but its pathogenesis remains elusive. Fibroblast growth factor 23 (FGF23) is increased in both renal dysfunction and cardiac dysfunction, and FGF receptor 4 (FGFR4) has been identified as a receptor for FGF23. Deficiency of FGF23 causes growth retardation and shortens the lifespan, but it is unclear whether excess FGF23 is detrimental in CRS. This study sought to investigate whether FGF23 plays an important role in CRS-induced renal fibrosis. A mo ...[more]

PMID: 33460402

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Project description:Background and objectivesAnemia is an early complication of CKD that is associated with increased morbidity and mortality. Prior data show associations between abnormal mineral metabolism markers and decreased erythropoiesis. However, few studies have investigated elevated fibroblast growth factor 23 as a risk factor for the development of anemia in patients with CKD.Design, setting, participants, & measurementsWe conducted a prospective cohort study of 3869 individuals with mild to severe CKD enrolled in the Chronic Renal Insufficiency Cohort Study between 2003 and 2008 and followed through 2013. We hypothesized that elevated baseline fibroblast growth factor 23 levels are associated with prevalent anemia, decline in hemoglobin over time, and development of incident anemia, defined as serum hemoglobin level <13 g/dl in men, serum hemoglobin level <12 g/dl in women, or use of erythropoietin stimulating agents.ResultsIn the 1872 of 3869 individuals who had prevalent anemia at baseline, mean age was 58 (11) years old, and mean eGFR was 39 (13) ml/min per 1.73 m2. Higher levels of fibroblast growth factor 23 were significantly associated with prevalent anemia (odds ratio per 1-SD increase in natural log-transformed fibroblast growth factor 23, 1.39; 95% confidence interval, 1.26 to 1.52), decline in hemoglobin over 4 years, and risk of incident anemia (hazard ratio per 1-SD increase in natural log-transformed fibroblast growth factor 23, 1.13; 95% confidence interval, 1.04 to 1.24; quartile 4 versus quartile 1: hazard ratio, 1.59; 95% confidence interval, 1.19 to 2.11) independent of demographic characteristics, cardiovascular disease risk factors, CKD-specific factors, and other mineral metabolism markers. The results of our prospective analyses remained unchanged after additional adjustment for time-varying eGFR.ConclusionsElevated fibroblast growth factor 23 is associated with prevalent anemia, change in hemoglobin over time, and development of anemia. Future studies are needed to elucidate the mechanisms for these associations.

Dataset Information

Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome.

Publications

Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome.

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