期刊
CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION
卷 28, 期 1, 页码 16-25出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MNH.0000000000000467
关键词
alpha-Klotho; bone; cardiovascular; fibroblast growth factor 23; fibroblast growth factor receptors; hypophosphatemia; innate immunity; kidney
资金
- National Institutes of Health (NIH) [1R01AR045955]
- NIAMS
Purpose of review The current review examines what is known about the FGF-23/alpha-Klotho co-dependent and independent pathophysiological effects, and whether FGF-23 and/or alpha-Klotho are potential therapeutic targets. Recent findings FGF-23 is a hormone derived mainly from bone, and alpha-Klotho is a transmembrane protein. Together they form a trimeric signaling complex with FGFRs in target tissues to mediate the physiological functions of FGF-23. Local and systemic factors control FGF-23 release from osteoblast/osteocytes in bone, and circulating FGF-23 activates FGFR/alpha-Klotho complexes in kidney proximal and distal renal tubules to regulate renal phosphate excretion, 1,25 (OH)(2)D metabolism, sodium and calcium reabsorption, and ACE2 and alpha-Klotho expression. The resulting bone-renal-cardiac-immune networks provide a new understanding of bone and mineral homeostasis, as well as identify other biological effects FGF-23. Direct FGF-23 activation of FGFRs in the absence of alpha-Klotho is proposed to mediate cardiotoxic and adverse innate immune effects of excess FGF-23, particularly in chronic kidney disease, but this FGF-23, alpha-Klotho-independent signaling is controversial. In addition, circulating soluble Klotho (sKl) released from the distal tubule by ectodomain shedding is proposed to have beneficial health effects independent of FGF-23. Summary Separation of FGF-23 and alpha-Klotho independent functions has been difficult in mammalian systems and understanding FGF-23/alpha-Klotho co-dependent and independent effects are incomplete. Antagonism of FGF-23 is important in treatment of hypophosphatemic disorders caused by excess FGF-23, but its role in chronic kidney disease is uncertain. Administration of recombinant sKl is an unproven therapeutic strategy that theoretically could improve the healt span and lifespan of patients with alpha-Klotho deficiency.
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