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

143 Scopus citations

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)2169-2175
Number of pages7
JournalJournal of the American Society of Nephrology
Volume25
Issue number10
DOIs
StatePublished - Oct 1 2014

ASJC Scopus subject areas

  • Nephrology

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    Lindberg, K., Amin, R., Moe, O. W., Hu, M. C., Erben, R. G., Wernerson, A. Ö., Lanske, B., Olauson, H., & Larsson, T. E. (2014). The kidney is the principal organ mediating Klotho effects. Journal of the American Society of Nephrology, 25(10), 2169-2175. https://doi.org/10.1681/ASN.2013111209