Format

Send to

Choose Destination
J Am Soc Nephrol. 2014 Oct;25(10):2169-75. doi: 10.1681/ASN.2013111209. Epub 2014 May 22.

The kidney is the principal organ mediating klotho effects.

Author information

1
Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm Sweden;
2
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
3
Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria;
4
Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden;
5
Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts; and.
6
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.

Abstract

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.

KEYWORDS:

calcium; hyperphosphatemia; mineral metabolism; vascular calcification

Comment in

PMID:
24854271
PMCID:
PMC4178446
DOI:
10.1681/ASN.2013111209
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center