Fibroblast growth factor 23 is induced by an activated renin–angiotensin–aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts
Autor: | Maren Leifheit-Nestler, Joerg Heineke, Beatrice Richter, Michael Klintschar, Julia Nespor, Felix Kirchhoff, Dieter Haffner, Birga Soetje |
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Rok vydání: | 2018 |
Předmět: |
Male
medicine.medical_specialty Cardiac fibrosis 030232 urology & nephrology SMAD 030204 cardiovascular system & hematology urologic and male genital diseases Renin-Angiotensin System 03 medical and health sciences 0302 clinical medicine Fibrosis Internal medicine medicine Humans Myocyte Myocytes Cardiac Renal Insufficiency Chronic Child Klotho Proteins Klotho Glucuronidase Retrospective Studies Transplantation business.industry Fibroblasts Prognosis medicine.disease Angiotensin II Up-Regulation Fibroblast Growth Factors Fibroblast Growth Factor-23 stomatognathic diseases Endocrinology Gene Expression Regulation Nephrology Case-Control Studies Female Myocardial fibrosis business Transforming growth factor |
Zdroj: | Nephrology Dialysis Transplantation. 33:1722-1734 |
ISSN: | 1460-2385 0931-0509 |
Popis: | Background Fibroblast growth factor 23 (FGF23) is discussed as a new biomarker of cardiac hypertrophy and mortality in patients with and without chronic kidney disease (CKD). We previously demonstrated that FGF23 is expressed by cardiac myocytes, enhanced in CKD and induces cardiac hypertrophy via activation of FGF receptor 4 independent of its co-receptor klotho. The impact of FGF23 on cardiac fibrosis is largely unknown. Methods By conducting a retrospective case-control study including myocardial autopsy samples from 24 patients with end-stage CKD and in vitro studies in cardiac fibroblasts and myocytes, we investigated the pro-fibrotic properties of FGF23. Results The accumulation of fibrillar collagens I and III was increased in myocardial tissue of CKD patients and correlated with dialysis vintage, klotho deficiency and enhanced cardiac angiotensinogen (AGT) expression. Using human fibrosis RT2 Profiler PCR array analysis, transforming growth factor (TGF)-β and its related TGF-β receptor/Smad complexes, extracellular matrix remodeling enzymes and pro-fibrotic growth factors were upregulated in myocardial tissue of CKD patients. FGF23 stimulated cell proliferation, migration, pro-fibrotic TGF-β receptor/Smad complexes and collagen synthesis in cultured cardiac fibroblasts. In isolated cardiac myocytes, FGF23 enhanced collagen remodeling, expression of pro-inflammatory genes and pro-survival pathways and induced pro-hypertrophic genes. FGF23 stimulated AGT expression in cardiac myocytes and angiotensin II and aldosterone, as components of the renin-angiotensin-aldosterone system (RAAS), induced FGF23 in cardiac myocytes. Conclusions Our data demonstrate that activated RAAS induces FGF23 expression in cardiac myocytes and thereby stimulates a pro-fibrotic crosstalk between cardiac myocytes and fibroblasts, which may contribute to myocardial fibrosis in CKD. |
Databáze: | OpenAIRE |
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