Klotho in health and disease.
OBJECTIVE
The klotho gene was originally identified as a putative aging-suppressor gene in mice that extended life span when overexpressed and induced a premature aging syndrome when disrupted. Subsequently, it became clear that the Klotho family of membrane proteins function as obligate co-receptors for endocrine fibroblast growth factors (FGFs) that regulate various metabolic processes. This review focuses on the Klotho-FGF23 endocrine system that maintains phosphate (Pi) homeostasis, and discusses the mechanism of action and the potential contribution of Klotho deficiency to acute kidney injury (AKI), chronic kidney disease (CKD) and cancer.


RESULTS
Klotho functions as a receptor for the phosphaturic hormone FGF23. Klotho deficiency induces resistance to FGF23 and predisposition to Pi retention, which represents a critical feature of pathophysiology of CKD. The extracellular domain of Klotho protein is subject to ectodomain shedding and released into the blood and urine. Secreted Klotho functions as a humoral factor that inhibits AKI, vascular calcification, renal fibrosis, and cancer metastasis in an FGF23-independent manner.


CONCLUSIONS
Various factors that affect Klotho expression have been identified. Prevention of Klotho decline and supplementation of Klotho can be a novel therapeutic strategy for many age-related diseases.
Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072, USA. Makoto.Kuro-o@UTSouthwestern.edu
Makoto
M
Kuro-o
D058186:Acute Kidney Injury / Q000378:metabolism; D000818:Animals; D002908:Chronic Disease; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000090265:Klotho Proteins; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010710:Phosphates / Q000378:metabolism; D015398:Signal Transduction
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins