title: Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression.
abstract: The kidney controls systemic calcium and phosphate levels and disturbances of its control mechanisms can lead to a variety of diseases. The insulin-sensitizing adipokine adiponectin is renoprotective and accelerates functional recovery following renal injury. However, unlike other adipokines, adiponectin is reduced in obesity. High adiponectin levels are also correlated with bone loss, suggestive of an additional action in mineral metabolism. Using knockout, wild-type, and adiponectin-overexpressing transgenic mice, we sought to identify the mechanistic basis for adiponectin's ability to regulate calcium and phosphate balance at the level of the kidney. Adiponectin knockout mice exhibited lower serum calcium, lower urinary calcium excretion, and markedly lower serum fibroblast growth factor 23 (FGF23) levels, although circulating klotho concentrations were significantly higher than in wild-type littermates. The transgenic mice exhibited lower bone mass and strength, particularly compared to adiponectin knockout mice. The transgenic mice were hyper-responsive to a 2% phosphate-enriched diet, exhibiting 2-fold higher serum FGF23 and concomitantly higher fractional phosphate excretion. These mice also excreted more calcium with calcium-enriched diet and had less renal klotho protein expression. In contrast, the knockout mice exhibited a smaller increase in FGF23 and maintained elevated klotho levels on both mineral challenges. Kidney-specific adiponectin expression in doxycycline-inducible adiponectin mice and adiponectin addition in vitro confirmed adiponectin's ability to reduce tubular epithelial cell klotho secretion. Thus, adiponectin alters calcium and phosphate balance and renal mineral excretion, in part, through klotho. This work highlights the profound effects of adipose tissue on renal function and has identified a new mechanism by which adiponectin may regulate bone mass.
authors.affiliation: Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Rutkowski
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Johanne
authors.initials: J
authors.lastname: Pastor
authors.affiliation: Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Sun K
authors.initials: SK
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: I Alexandru
authors.initials: IA
authors.lastname: Bobulescu
authors.affiliation: The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
authors.affiliation: Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address: Philipp.Scherer@utsouthwestern.edu.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D052242:Adiponectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001696:Biomechanical Phenomena; D002136:Calcium, Dietary / Q000097:blood / Q000378:metabolism* / Q000652:urine; D003094:Collagen / Q000378:metabolism; D004285:Dogs; D005269:Femur / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D005355:Fibrosis; D005838:Genotype; D005966:Glucuronidase / Q000097:blood* / Q000235:genetics; D006706:Homeostasis; D006728:Hormones / Q000097:blood; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism; D000090265:Klotho Proteins; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D018345:Mice, Knockout; D010012:Osteogenesis; D010641:Phenotype; D010710:Phosphates / Q000097:blood / Q000378:metabolism* / Q000652:urine; D016226:Phosphorus, Dietary / Q000097:blood / Q000378:metabolism* / Q000652:urine; D065667:Renal Elimination; D013131:Spine / Q000378:metabolism; D014162:Transfection
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D002136:Calcium, Dietary; C000717428:Fgf23 protein, mouse; D006728:Hormones; D010710:Phosphates; D016226:Phosphorus, Dietary; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D003094:Collagen; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: FGF23; calcium; mineral metabolism; obesity; phosphate