Leifheit-Nestler Maren, Richter Beatrice, Basaran Melis, Nespor Julia, Vogt Isabel, Alesutan Ioana, Voelkl Jakob, Lang Florian, Heineke Joerg, Krick Stefanie, Haffner Dieter
Department of Pediatric Kidney, Liver and Metabolic Diseases, Pediatric Research Center, Hannover Medical School, Hannover, Germany.
Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Front Endocrinol (Lausanne). 2018 Jun 21;9:333. doi: 10.3389/fendo.2018.00333. eCollection 2018.
Clinical and experimental studies indicate a possible link between high serum levels of fibroblast growth factor 23 (FGF23), phosphate, and parathyroid hormone (PTH), deficiency of active vitamin D (1,25D) and klotho with the development of pathological cardiac remodeling, i.e., left ventricular hypertrophy and myocardial fibrosis, but a causal link has not been established so far. Here, we investigated the cardiac phenotype in klotho hypomorphic () mice and mice, two mouse models of elevated FGF23 levels and klotho deficiency, but differing in parameters of mineral metabolism, by using histology, quantitative real-time PCR, immunoblot analysis, and serum and urine biochemistry. Additionally, the specific impact of calcium, phosphate, PTH, and 1,25D on hypertrophic growth of isolated neonatal rat cardiac myocytes was investigated . mice displayed high serum Fgf23 levels, increased relative heart weight, enhanced cross-sectional area of individual cardiac myocytes, activated cardiac Fgf23/Fgf receptor (Fgfr) 4/calcineurin/nuclear factor of activated T cell (NFAT) signaling, and induction of pro-hypertrophic NFAT target genes including , brain natriuretic peptide (), and atrial natriuretic peptide () as compared to corresponding wild-type (WT) mice. Investigation of fibrosis-related molecules characteristic for pathological cardiac remodeling processes demonstrated ERK1/2 activation and enhanced expression of Tgf-β1, , and Mmp2 in mice than in WT mice. In contrast, despite significantly elevation of serum and cardiac Fgf23, and reduced renal expression, mice showed no signs of pathological cardiac remodeling. mice showed enhanced serum calcium and phosphate levels, while mice showed unchanged serum calcium levels, lower serum phosphate, and elevated serum iPTH concentrations compared to corresponding WT mice. In cultured cardiac myocytes, treatment with both calcium or phosphate significantly upregulated endogenous mRNA expression and stimulated hypertrophic cell growth and expression of pro-hypertrophic genes. The treatment with PTH induced hypertrophic cell growth only, and stimulation with 1,25D had no significant effects. In conclusion, our data indicate that mice, in contrast to mice appear to be protected from pathological cardiac remodeling during conditions of high FGF23 levels and klotho deficiency, which may be due, at least in part, to differences in mineral metabolism alterations, i.e., hypophosphatemia and lack of hypercalcemia.
临床和实验研究表明，血清中高成纤维细胞生长因子23（FGF23）、磷酸盐和甲状旁腺激素（PTH）水平、活性维生素D（1,25D）缺乏以及klotho缺乏与病理性心脏重塑的发生发展之间可能存在联系，即左心室肥厚和心肌纤维化，但迄今为止尚未建立因果关系。在此，我们通过组织学、定量实时PCR、免疫印迹分析以及血清和尿液生物化学方法，研究了klotho低表达（）小鼠和小鼠这两种FGF23水平升高和klotho缺乏的小鼠模型的心脏表型，这两种模型在矿物质代谢参数上有所不同。此外，还研究了钙、磷酸盐、PTH和1,25D对分离的新生大鼠心肌细胞肥大生长的具体影响。与相应的野生型（WT）小鼠相比，小鼠血清Fgf23水平升高，相对心脏重量增加，单个心肌细胞横截面积增大，心脏Fgf23/Fgf受体（Fgfr）4/钙调神经磷酸酶/活化T细胞核因子（NFAT）信号通路激活，以及诱导包括、脑钠肽（）和心钠素（）在内的促肥大NFAT靶基因表达。对病理性心脏重塑过程中特征性纤维化相关分子的研究表明，与WT小鼠相比，小鼠中ERK1/2激活以及Tgf-β1、和Mmp2表达增强。相比之下，尽管小鼠血清和心脏Fgf23显著升高，肾表达降低，但未表现出病理性心脏重塑的迹象。与相应的WT小鼠相比，小鼠血清钙和磷酸盐水平升高，而小鼠血清钙水平未改变，血清磷酸盐降低，血清iPTH浓度升高。在培养的心肌细胞中，钙或磷酸盐处理均显著上调内源性mRNA表达，并刺激肥大细胞生长和促肥大基因表达。PTH处理仅诱导肥大细胞生长，而1,25D刺激无显著影响。总之，我们的数据表明，与小鼠相比，小鼠在FGF23水平升高和klotho缺乏的情况下似乎免受病理性心脏重塑的影响，这可能至少部分归因于矿物质代谢改变的差异即低磷血症和无高钙血症。
