The kidney is the principal organ mediating Klotho effects

Karolina Lindberg, Risul Amin, Orson W Moe, Ming C Hu, Reinhold G. Erben, Annika Östman Wernerson, Beate Lanske, Hannes Olauson, Tobias E. Larsson

Research output: Contribution to journalArticle

133 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)210-225
Number of pages16
JournalHistoric Environment: Policy and Practice
Volume5
Issue number2
DOIs
StatePublished - Jul 1 2014

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Kidney
Organs
Mouse
Membrane
Manifestation
Phenotype
Premature Death
Gene
Protein
Histology
Comparative Analysis
Cleavage

ASJC Scopus subject areas

  • History
  • Conservation
  • Archaeology

Cite this

The kidney is the principal organ mediating Klotho effects. / Lindberg, Karolina; Amin, Risul; Moe, Orson W; Hu, Ming C; Erben, Reinhold G.; Wernerson, Annika Östman; Lanske, Beate; Olauson, Hannes; Larsson, Tobias E.

In: Historic Environment: Policy and Practice, Vol. 5, No. 2, 01.07.2014, p. 210-225.

Research output: Contribution to journalArticle

Lindberg, K, Amin, R, Moe, OW, Hu, MC, Erben, RG, Wernerson, AÖ, Lanske, B, Olauson, H & Larsson, TE 2014, 'The kidney is the principal organ mediating Klotho effects', Historic Environment: Policy and Practice, vol. 5, no. 2, pp. 210-225. https://doi.org/10.1681/ASN.2013111209
Lindberg, Karolina ; Amin, Risul ; Moe, Orson W ; Hu, Ming C ; Erben, Reinhold G. ; Wernerson, Annika Östman ; Lanske, Beate ; Olauson, Hannes ; Larsson, Tobias E. / The kidney is the principal organ mediating Klotho effects. In: Historic Environment: Policy and Practice. 2014 ; Vol. 5, No. 2. pp. 210-225.
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