TY - JOUR
T1 - The kidney is the principal organ mediating Klotho effects
AU - Lindberg, Karolina
AU - Amin, Risul
AU - Moe, Orson W
AU - Hu, Ming C
AU - Erben, Reinhold G.
AU - Wernerson, Annika Östman
AU - Lanske, Beate
AU - Olauson, Hannes
AU - Larsson, Tobias E.
N1 - Publisher Copyright:
Copyright © 2014 by the American Society of Nephrology.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84915782238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84915782238&partnerID=8YFLogxK
U2 - 10.1681/ASN.2013111209
DO - 10.1681/ASN.2013111209
M3 - Article
C2 - 24854271
AN - SCOPUS:84915782238
SN - 1046-6673
VL - 25
SP - 2169
EP - 2175
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 10
ER -