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Hyperaldosteronism in Klotho-deficient mice

  • Klotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25- dihydroxyvitamin-D-3 [1,25(OH)(2)D-3]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca2+ reabsorption. Klotho hypomorphic mice (klotho(hm)) suffer from severe growth deficit, rapid aging, and early death, events largely reversed by a vitamin D-deficient diet. The present study explored the role of Klotho deficiency in mineral and electrolyte metabolism. To this end, klothohm mice and wild-type mice (klotho(+/+)) were subjected to a normal (D+) or vitamin D-deficient (D-) diet or to a vitamin D-deficient diet for 4 wk and then to a normal diet (D-/+). At the age of 8 wk, body weight was significantly lower in klotho(hm)D(+) mice than in klotho(+/ +)D(+) mice, klotho(hm)D(-) mice, and klotho(hm)D(-/+) mice. Plasma concentrations of 1,25(OH)(2)D-3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho(hm)D(+) mice thanKlotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25- dihydroxyvitamin-D-3 [1,25(OH)(2)D-3]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca2+ reabsorption. Klotho hypomorphic mice (klotho(hm)) suffer from severe growth deficit, rapid aging, and early death, events largely reversed by a vitamin D-deficient diet. The present study explored the role of Klotho deficiency in mineral and electrolyte metabolism. To this end, klothohm mice and wild-type mice (klotho(+/+)) were subjected to a normal (D+) or vitamin D-deficient (D-) diet or to a vitamin D-deficient diet for 4 wk and then to a normal diet (D-/+). At the age of 8 wk, body weight was significantly lower in klotho(hm)D(+) mice than in klotho(+/ +)D(+) mice, klotho(hm)D(-) mice, and klotho(hm)D(-/+) mice. Plasma concentrations of 1,25(OH)(2)D-3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. Plasma volume was significantly smaller in klotho(hm)D(-/+) mice, and plasma urea, Ca2+, phosphate and Na+, but not K+ concentrations were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. The differences were partially abrogated by a vitamin D-deficient diet. Moreover, the hyperaldosteronism was partially reversed by Ca2+-deficient diet. Ussing chamber experiments revealed a marked increase in amiloride-sensitive current across the colonic epithelium, pointing to enhanced epithelial sodium channel (ENaC) activity. A salt-deficient diet tended to decrease and a salt-rich diet significantly increased the life span of klotho(hm)D(+) mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)(2)D-3 in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span.show moreshow less

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Metadaten
Author:Stephanie S. Fischer, Daniela S. Kempe, Christina B. Leibrock, Rexhep Rexhepaj, Balasaheb Siraskar, Krishna M. Boini, Teresa F. Ackermann, Michael Foeller, Berthold HocherGND, Kevin P. Rosenblatt, Makoto Kuro-o, Florian Lang
URL:http://ajprenal.physiology.org/
DOI:https://doi.org/10.1152/ajprenal.00233.2010
ISSN:1931-857X
Document Type:Article
Language:English
Year of first Publication:2010
Year of Completion:2010
Release Date:2017/03/25
Source:American journal of physiology : renal physiology. - ISSN 1931-857X. - 299 (2010), 5, S. F1171 - F1177
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
Peer Review:Referiert