ABSTRACT
Klotho gene mutation leads to a syndrome strangely resembling chronic kidney disease patients undergoing dialysis with multiple accelerated age-related disorders, including hypoactivity, sterility, skin thinning, muscle atrophy, osteoporosis, vascular calcifications, soft-tissue calcifications, defective hearing, thymus atrophy, pulmonary emphysema, ataxia, and abnormalities of the pituitary gland, as well as hypoglycemia, hyperphosphatemia, and paradoxically high-plasma calcitriol levels. Conversely, mice overexpressing klotho show an extended existence and a slow aging process through a mechanism that may involve the induction of a state of insulin and oxidant stress resistance. Two molecules are produced by the klotho gene, a membrane bound form and a circulating form. However, their precise biological roles and molecular functions have been only partly deciphered. Klotho can act as a circulating factor or hormone, which binds to a not yet identified high-affinity receptor and inhibits the intracellular insulin/insulin-like growth factor-1 (IGF-1) signaling cascade; klotho can function as a novel beta-glucuronidase, which deglycosylates steroid beta-glucuronides and the calcium channel transient receptor potential vallinoid-5 (TRPV5); as a cofactor essential for the stimulation of fibroblast growth factor (FGF) receptor by FGF23. The two last functions have propelled klotho to the group of key factors regulating mineral and vitamin D metabolism, and have also stimulated the interest of the nephrology community. The purpose of this review is to provide a nephrology-oriented overview of klotho and its potential implications in normal and altered renal function states.
Subject(s)
Aging/physiology , Glucuronidase/physiology , Kidney/metabolism , Minerals/metabolism , Vitamin D/metabolism , Aging/metabolism , Animals , Bone and Bones/metabolism , Fibroblast Growth Factor-23 , Glucuronidase/genetics , Glucuronidase/metabolism , Humans , Klotho Proteins , RNA, Messenger/metabolismABSTRACT
Serum parathyroid hormone (PTH) is a recognized marker of bone remodeling in patients with renal osteodystrophy. However, identification of N-terminal truncated PTH fragments and a new form of PTH that interfere with second-generation PTH assays may be responsible for the great variability of PTH values and the difficulties of implementing the recommendations of the National Kidney Foundation/Kidney Disease Outcomes Quality Initiative.
