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

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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.