University of Tennessee Health Science Center, Medicine-Nephrology, Memphis, Tennessee, United States of America.
PLoS One. 2012;7(9):e44161. doi: 10.1371/journal.pone.0044161. Epub 2012 Sep 6.
Elevations of circulating Fibroblast growth factor 23 (FGF23) are associated with adverse cardiovascular outcomes and progression of renal failure in chronic kidney disease (CKD). Efforts to identify gene products whose transcription is directly regulated by FGF23 stimulation of fibroblast growth factor receptors (FGFR)/α-Klotho complexes in the kidney is confounded by both systemic alterations in calcium, phosphorus and vitamin D metabolism and intrinsic alterations caused by the underlying renal pathology in CKD. To identify FGF23 responsive genes in the kidney that might explain the association between FGF23 and adverse outcomes in CKD, we performed comparative genome wide analysis of gene expression profiles in the kidney of the Collagen 4 alpha 3 null mice (Col4a3(-/-)) model of progressive kidney disease with kidney expression profiles of Hypophosphatemic (Hyp) and FGF23 transgenic mouse models of elevated FGF23. The different complement of potentially confounding factors in these models allowed us to identify genes that are directly targeted by FGF23. This analysis found that α-Klotho, an anti-aging hormone and FGF23 co-receptor, was decreased by FGF23. We also identified additional FGF23-responsive transcripts and activation of networks associated with renal damage and chronic inflammation, including lipocalin 2 (Lcn2), transforming growth factor beta (TGF-β) and tumor necrosis factor-alpha (TNF-α) signaling pathways. Finally, we found that FGF23 suppresses angiotensin-converting enzyme 2 (ACE2) expression in the kidney, thereby providing a pathway for FGF23 regulation of the renin-angiotensin system. These gene products provide a possible mechanistic links between elevated FGF23 and pathways responsible for renal failure progression and cardiovascular diseases.
循环成纤维细胞生长因子 23（FGF23）水平升高与慢性肾脏病（CKD）患者的心血管不良结局和肾功能衰竭进展有关。试图鉴定其转录受 FGF23 刺激成纤维细胞生长因子受体（FGFR）/α-Klotho 复合物直接调控的基因产物，但受到钙、磷和维生素 D 代谢的系统改变以及 CKD 潜在肾病理学引起的内在改变的影响。为了鉴定肾脏中 FGF23 反应基因，这些基因可能可以解释 FGF23 与 CKD 不良结局之间的关联，我们对进行性肾病的胶原 4α3 缺失（Col4a3(-/-)）小鼠模型和低磷血症（Hyp）及 FGF23 转基因小鼠模型的肾脏基因表达谱进行了比较全基因组分析。这些模型中不同的潜在混杂因素使我们能够鉴定出直接受 FGF23 靶向的基因。该分析发现，抗衰老激素和 FGF23 共受体α-Klotho 受 FGF23 下调。我们还鉴定了其他 FGF23 反应转录本，并激活了与肾脏损伤和慢性炎症相关的网络，包括脂质运载蛋白 2（Lcn2）、转化生长因子-β（TGF-β）和肿瘤坏死因子-α（TNF-α）信号通路。最后，我们发现 FGF23 抑制肾脏中的血管紧张素转换酶 2（ACE2）表达，从而为 FGF23 调节肾素-血管紧张素系统提供了一种途径。这些基因产物为 FGF23 水平升高与导致肾衰竭进展和心血管疾病的途径之间提供了可能的机制联系。
