ORCID Profile
0000-0002-6854-4261
Current Organisation
Université Paris Descartes
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Publisher: Elsevier BV
Date: 2009
DOI: 10.1053/J.JRN.2008.10.018
Abstract: The discovery that two recently identified molecules, klotho and fibroblast growth factor 23 (FGF23), played an important role in calcium, phosphate, and vitamin D metabolism has transformed our traditional physiological view in which bone and mineral homeostasis was mainly regulated by parathyroid hormone, vitamin D, and calcitonin, according to mineral body needs. FGF23 is a 251-amino acid secreted protein produced by osteoblasts and osteocytes in bone following the stimulation by phosphate and vitamin D or the inhibition by dentin matrix protein 1. Originally isolated from tumoral cells of patients with tumor-induced osteomalacia and hypophosphatemia, FGF23 inhibits phosphate reabsorption in renal proximal tubular cells and 1alpha-hydroxylase activity, resulting in decreased synthesis of calcitriol. To exert these actions, FGF23 requires the conversion, by klotho, of the canonical FGF receptor 1 (IIIc) in a specific high affinity FGF23 receptor. On the other hand, klotho is a putative antiaging gene identified in 1997 when a particular mouse strain, created by random insertion mutagenesis, was found to be short-lived and displayed premature atherosclerosis, osteopenia, skin atrophy, pulmonary emphysema, hyperphosphatemia, hypercalcemia, and high serum calcitriol levels. The gene of klotho encodes a 1012-amino acid cell-surface protein with a short cytoplasmic tail and an extracellular domain that consists in tandem duplicated copies of a beta-glucuronidase-like sequence, which can be released into the circulation as soluble forms after being cleaved by metalloproteinases such as ADAM10 and ADAM17. By modulating FGF23 action, klotho regulates urinary phosphate excretion and calcitriol synthesis. By virtue of its beta-glucuronidase activity, klotho deglycosylates the calcium channel TRPV5 (transient receptor potential vallinoid-5) and regulates urinary calcium excretion. klotho also binds to Na(+),K(+)-ATPase in parathyroid cells and regulates calcium-stimulated PTH secretion. Finally, klotho extends life span via several mechanisms, including the reduction of calcitriol synthesis, serum calcium, and phosphorus levels the induction of insulin resistance and by increasing the resistance to oxidative stress.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2005
DOI: 10.1097/01.MNH.0000172716.41853.1E
Abstract: We summarize the most recent findings on the proteins that interact with sodium/inorganic phosphate (Na/Pi) cotransporters, the factors that regulate Pi homeostasis and their role in pathology. Studies in animal models and cell lines identified proteins mandatory to correct trafficking of the kidney-specific Na/Pi cotransporter NPT2a and its control by the parathyroid hormone. Expression of the intestinal cotransporter NPT2b is controlled by calcitriol, the ubiquitin ligase Nedd-4 and the serum glucocorticoid inducible kinase. Recent data confirm that fibroblast growth factor 23 plays a central role in the control of Pi homeostasis. Mice disrupted for or overexpressing this gene exhibit significant alteration of Pi transport and calcitriol metabolism. In humans, fibroblast growth factor 23 mutations are responsible for autosomal hypophosphataemic rickets or tumoral calcinosis. This gene also seems to be involved in hyperparathyroidism in patients with chronic kidney disease. Several new phosphaturic factors have been identified. Moderate increases in serum Pi concentration may have deleterious effects on lifespan in humans with chronic kidney disease. Disruption of the Klotho gene in mice is associated with hyperphosphataemia and decreased lifespan. Polymorphisms in this gene, in humans and in mice, influence vascular calcification and survival. Pi homeostasis depends on the activity of Na/Pi cotransporters in intestine and kidney. Na/Pi transporter activity is regulated by cellular and endocrine factors, among which fibroblast growth factor 23 plays a central role. Adequate control of Pi homeostasis is crucial, as a moderate increase in serum Pi concentration and polymorphisms in genes involved in Pi metabolism may influence the aging process and lifespan.
Publisher: Massachusetts Medical Society
Date: 11-09-2008
Publisher: Public Library of Science (PLoS)
Date: 13-06-2013
Publisher: Elsevier BV
Date: 11-2010
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1053/J.JRN.2006.01.011
Abstract: Secondary hyperparathyroidism (SHPT) is a common and serious complication of chronic kidney disease (CKD). It affects more than 300,000 end-stage renal disease patients treated by dialysis and probably more than 3 million patients with CKD worldwide. For a long time, traditional therapies for SHPT had consisted of correcting the hypocalcemia using calcium salts and vitamin D derivatives, preventing the hyperphosphatemia by calcium- or aluminum-containing intestinal phosphate binders, and recently by using no metal-containing intestinal phosphate binders however, these therapies are limited by the occurrence of hypercalcemia, hyperphosphatemia, and the lack of specificity and long-term efficacy. Moreover, surgical parathyroidectomy (PTX), which remains the gold standard therapy, is not exempt from risk. PTX exposes patients to anesthesia risks, presurgical and postsurgical complications, and in many cases a permanent state of hypoparathyroidism. Thus, the medical treatment of SHPT became an ideal target for the development of new therapies and strategies. The purpose of this article is to provide an overview of these new therapies, including vitamin D analogs, intestinal phosphate binders, calcimimetics, parathyroidectomies, tyrosine kinase inhibitors, azydothymidine, anticalcineurins, N-terminal truncated parathyroid hormone fragments, bisphosphonates, calcitonin, osteoprotegerin, and others. The use of these new therapies alone or in combination may help to optimize the future treatment of SHPT in CKD patients.
Publisher: Public Library of Science (PLoS)
Date: 10-04-2012
Publisher: Elsevier BV
Date: 11-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2004
DOI: 10.1097/00041552-200411000-00015
Abstract: We discuss how recent findings obtained in disorders of phosphate metabolism in humans and in animal models have provided insights into the pathogenesis of renal stone formation and bone demineralization. Mice that are null for the sodium-phosphate cotransporter (NPT)2a gene (NPT2a(-/-) mice) exhibit hypophosphataemia, increased urinary phosphate excretion, hypercalciuria and nephrolithiasis, but no bone demineralization. Mice null for the sodium-hydrogen exchanger regulatory factor (NHERF)1 (NHERF1(-/-) mice) also exhibit hypophosphataemia and increased renal phosphate excretion with decreased renal NPT2a expression, but they present with a severe sex-dependent bone demineralization. Heterozygous loss-of-function mutations in the NPT2a gene in humans induce hypophosphataemia, increased urinary phosphate excretion, hypercalciuria, nephrolithiasis in males (to date) and bone demineralization of variable severity in both sexes. Patients and experimental animals with increased circulating levels of fibroblast growth factor 23 present with hypophosphataemia, increased urinary phosphate excretion, inappropriate calcitriol synthesis and rickets/osteomalacia, but no nephrolithiasis except when treated. Low-phosphate diet in spontaneously hypercalciuric rats and disruption of the 1-alpha-hydroxylase gene in NPT2a mice prevent renal stone formation. Increased urinary phosphate excretion is a risk factor for renal calcium stone formation when it is associated with hypercalciuria. As yet undefined interplay between NPT2a, NHERF1 and possibly other cotransporters or associated proteins in bone cells may account for the ersity of bone phenotypes observed in disorders of phosphate metabolism with impaired renal phosphate reabsorption. The pathogenesis of both renal stone and bone demineralization appear to be affected by species, sex and mutation type, among other factors.
Publisher: Elsevier BV
Date: 04-2007
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.
No related grants have been discovered for Gerard Friedlander.