XLV ERA-EDTA CONGRESS

DAY BY DAY

CONGRESS HIGHLIGHTS

Klotho as a regulator of fibroblast growth factor signalling and phosphate/calcium metabolism

Makoto Kuro-o

University of Texas Southwestern Medical Center at Dallas
MAY 11th - PLENARY LECTURE 1 - HALL A1 09:45 - 10:30

Klotho, an anti-aging protein, is found to control kidney function to maintain phosphate homeostasis.
The Klotho gene was discovered in 1997 that accelerated aging when disrupted in mice. The gene was named after one of the mythical Greek fates who spins the thread of life. Mice defective in Klotho gene expression appeared normal until 3-4 weeks of age. At that time they began to show signs of aging, such as skin atrophy, cognition impairment, hearing loss, osteoporosis, vascular calcification, and pulmonary emphysema. The mice died prematurely at about two months, while normal mice lived more than two years on average. In contrast, transgenic mice that carry extra copies of the Klotho gene lived longer than normal mice. Thus, the Klotho gene functions as an aging-suppressor gene in mice that prolongs life when overexpressed and accelerates aging when disrupted. Klotho is found in humans as well. The human Klotho gene polymorphisms has been associated with life span and common age-related disorders such as stroke, coronary artery disease, and osteoporosis, suggesting that Klotho is involved in aging processes not only in mice but also in humans. However, the molecular mechanism by which Klotho controls aging has not been clear.
Fibroblast growth factor-23 (FGF23) was identified as a bone-derived hormone that promotes renal phosphate excretion. Curiously, mice lacking FGF23 displayed aging-like symptoms identical with those observed in mice lacking Klotho. Recent studies have revealed that this is because Klotho is required for FGF23 to activate FGF receptors: Klotho forms a complex with FGF receptors to increase their ability to bind FGF23. In fact, defects in Klotho or FGF23 in mice and humans result in impaired renal phosphate excretion and hyperphosphatemia. Thus, Klotho and FGF23 have emerged as essential components of the novel bone-kidney endocrine axis that regulates phosphate metabolism.
Importantly, restriction of dietary phosphate in mice lacking Klotho or FGF23 rescues not only hyperphosphatemia but also many signs of aging, indicating that phosphate retention accelerated aging. The molecular mechanism behind phosphate toxicity remains to be determined.
Phosphate retention and resulting hyperphosphatemia has been identified as an independent risk of death in people with chronic kidney disease (CKD). More than 20 million Americans, or 1 in 9 adult Americans, have CKD, which can result in renal failure and is increasingly recognized as a global public health problem in aging society. In fact, control of blood phosphate levels has been proposed as one of the most important therapeutic goals for improving life expectancy of CKD patients. Further studies on the Klotho-FGF23 system are expected to identify novel targets for therapeutic intervention in CKD.