Endothelins and underlying signaling as regulators of fibroblast growth factor 23 (FGF23)

成纤维细胞生长因子23 （FGF23）是一种由骨细胞产生的蛋白质激素。它刺激肾磷酸盐排泄，抑制骨化三醇、活性维生素D的形成，诱导左心肥厚。肾脏作用，而不是心脏作用需要跨膜Klotho作为FGF23的共受体。Klotho或FGF23缺乏导致高磷血症，骨化三醇水平强烈升高并伴有大量钙化，以及快速衰老，伴有人类典型的衰老相关疾病的早期发作，以及寿命非常短。血浆FGF23水平升高可在肾脏和心脏疾病中发现，并与疾病活动性和死亡率相关。已知的FGF23产生的调节因子包括骨化三醇、甲状旁腺激素、炎症、食物磷酸盐、铁状态以及AMPK依赖性激酶AMPK和胰岛素依赖性PI3激酶通过转录因子FOXO1信号传导。内皮素-1是一种由内皮细胞产生的肽激素，主要作用于血管和血压，也能激活fox01。FOXO1的其他调节因子包括糖皮质激素和p38MAPK（一种由细胞应激激活的蛋白激酶）。糖皮质激素影响内皮素-1合成，p38MAPK影响糖皮质激素的作用。该项目旨在阐明(i)内皮素和内皮素B受体（ETB）对FGF23形成和钙/磷酸盐稳态的影响，（ii）糖皮质激素与FGF23产生的相关性，（iii） p38丝裂原活化激酶（p38MAPK）对FGF23合成的调节及其与钙/磷酸盐稳态的相关性，以及（iv）内皮素/糖皮质激素/p38MAPK对FGF23产生影响的确切分子机制。我们的项目可能有助于确定已经存在的用于患者的药物激动剂和拮抗剂的FGF23形成的新调节剂。因此，我们的研究不仅可以为肾病或心脏病患者提供新的治疗选择，也可以为普通人群提供新的治疗选择。

Fibroblast growth factor 23 (FGF23) is a proteohormone produced by osteocytes. It stimulates renal phosphate excretion, inhibits the formation of calcitriol, active vitamin D, and induces left heart hypertrophy. The renal, but not the cardiac effects require transmembrane Klotho as a co-receptor for FGF23. Klotho or FGF23 deficiency leads to hyperphosphatemia, strongly elevated calcitriol levels with massive calcification, as well as to rapid aging with the early onset of aging-associated diseases also typical of humans, and a very short life span. Elevated FGF23 plasma levels are found in kidney and cardiac diseases and correlate with disease activity and mortality. Known regulators of FGF23 production include calcitriol, parathyroid hormone, inflammation, alimentary phopshate, the iron status as well as AMPK-dependent kinase AMPK and insulin-dependent PI3 kinase signaling through transcription factor FOXO1 as we could demonstrate. Endothelin-1, a peptide hormone produced by endothelial cells with predominant effects on the vessels and blood pressure, also activates FOXO1. Futher regulators of FOXO1 include glucocorticoids and p38MAPK, a protein kinase activated by cellular stress. Glucocortiocids influence Endothelin-1 synthesis, and p38MAPK impacts on glucocorticoid effects. This project is supposed to elucidate (i) the impact of endothelins and the endothelin B receptor (ETB) on the formation of FGF23 and calcium/phosphate homeostasis, (ii) the relevance of glucocorticoids for FGF23 production, (iii) the regulation of FGF23 synthesis by p38 mitogen-activated kinase (p38MAPK) and its relevance for calcium/phosphate homeostasis, and (iv) the exact molecular mechanism of the endothelin/glucocorticoid/p38MAPK effects on FGF23 production. Our project may help identify novel modulators of FGF23 formation for which pharmacological agonist and antagonists, that are used in patients, already exist. Therefore our research may result in novel therapeutic options not only for patients with kidney or heart diseases, but also for the general population.