Department of Pediatric Kidney, Liver and Metabolic Diseases, Pediatric Research Center, Hannover Medical School, Hannover, Germany.
Department of Medicine and Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA.
Nephrol Dial Transplant. 2018 Oct 1;33(10):1722-1734. doi: 10.1093/ndt/gfy006.
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.
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.
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.
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.
成纤维细胞生长因子 23（FGF23）被认为是慢性肾脏病（CKD）患者和非 CKD 患者心肌肥大和死亡率的新生物标志物。我们之前的研究表明，FGF23 由心肌细胞表达，在 CKD 中增强，并通过激活 FGFR4 诱导心肌肥大，而不依赖其共受体 klotho。FGF23 对心肌纤维化的影响尚不清楚。
通过进行回顾性病例对照研究，包括 24 例终末期 CKD 患者的心肌尸检样本和心脏成纤维细胞和心肌细胞的体外研究，我们研究了 FGF23 的促纤维化特性。
CKD 患者心肌组织中纤维胶原 I 和 III 的积累增加，与透析龄、klotho 缺乏和增强的心脏血管紧张素原（AGT）表达相关。使用人纤维化 RT2 Profiler PCR 阵列分析，转化生长因子（TGF）-β及其相关 TGF-β受体/Smad 复合物、细胞外基质重塑酶和促纤维化生长因子在 CKD 患者心肌组织中上调。FGF23 刺激培养的心脏成纤维细胞增殖、迁移、促纤维化 TGF-β受体/Smad 复合物和胶原合成。在分离的心肌细胞中，FGF23 增强胶原重塑、炎症基因和生存途径的表达，并诱导促肥大基因。FGF23 刺激心肌细胞中 AGT 的表达，而肾素-血管紧张素-醛固酮系统（RAAS）的组成部分血管紧张素 II 和醛固酮诱导心肌细胞中 FGF23 的表达。
我们的数据表明，激活的 RAAS 诱导心肌细胞中 FGF23 的表达，从而刺激心肌细胞和成纤维细胞之间的促纤维化相互作用，这可能导致 CKD 中的心肌纤维化。
