The kidney is the principal organ mediating klotho effects.
Klotho was discovered as an antiaging gene, and α-Klotho (Klotho) is expressed in multiple tissues with a broad set of biologic functions. Membrane-bound Klotho binds fibroblast growth factor 23 (FGF23), but a soluble form of Klotho is also produced by alternative splicing or cleavage of the extracellular domain of the membrane-bound protein. The relative organ-specific contributions to the levels and effects of circulating Klotho remain unknown. We explored these issues by generating a novel mouse strain with Klotho deleted throughout the nephron (Six2-KL(-/-)). Klotho shedding from Six2-KL(-/-) kidney explants was undetectable and the serum Klotho level was reduced by approximately 80% in Six2-KL(-/-) mice compared with wild-type littermates. Six2-KL(-/-) mice exhibited severe growth retardation, kyphosis, and premature death, closely resembling the phenotype of systemic Klotho knockout mice. Notable biochemical changes included hyperphosphatemia, hypercalcemia, hyperaldosteronism, and elevated levels of 1,25-dihydroxyvitamin D and Fgf23, consistent with disrupted renal Fgf23 signaling. Kidney histology demonstrated interstitial fibrosis and nephrocalcinosis in addition to absent dimorphic tubules. A direct comparative analysis between Six2-KL(-/-) and systemic Klotho knockout mice supports extensive, yet indistinguishable, extrarenal organ manifestations. Thus, our data reveal the kidney as the principal contributor of circulating Klotho and Klotho-induced antiaging traits.
Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm Sweden;
Karolina
K
Lindberg
Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm Sweden;
Risul
R
Amin
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
Orson W
OW
Moe
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
Ming-Chang
MC
Hu
Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria;
Reinhold G
RG
Erben
Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden;
Annika
A
Östman Wernerson
Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts; and.
Beate
B
Lanske
Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm Sweden;
Hannes
H
Olauson
Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm Sweden; Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden tobias.larsson@ki.se.
Tobias E
TE
Larsson
D000375:Aging / Q000378:metabolism; D000818:Animals; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005966:Glucuronidase / Q000502:physiology*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D018345:Mice, Knockout
C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
calcium; hyperphosphatemia; mineral metabolism; vascular calcification