Hyperaldosteronism in klotho-deficient mice

Stephanie S. Fischer, Daniela S. Kempe, Christina B. Leibrock, Rexhep Rexhepaj, Balasaheb Siraskar, Krishna M. Boini, Teresa F. Ackermann, Michael Föller, Berthold Hocher, Kevin P. Rosenblatt, Makoto Kuro-o, Florian Lang

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Klotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25-dihydroxyvitamin-D3 [1,25(OH) 2D3]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca2+ reabsorption. Klotho hypomorphic mice (klothohm) 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, klotho hm 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 hmD+ mice than in klotho+/+D+ mice, klothohmD- mice, and klothohmD-/+ mice. Plasma concentrations of 1,25(OH)2D3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klothohmD+ mice than in klotho+/+D+ mice. Plasma volume was significantly smaller in klothohmD-/+ mice, and plasma urea, Ca2+, phosphate and Na+, but not K+ concentrations were significantly higher in klothohmD+ 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 klothohmD+ mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)2D 3 in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span.

Original languageEnglish (US)
Pages (from-to)F1171-F1177
JournalAmerican Journal of Physiology - Renal Physiology
Volume299
Issue number5
DOIs
StatePublished - Nov 2010

Keywords

  • Calcitriol
  • Calcium
  • Cell volume
  • Phosphate
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Fischer, S. S., Kempe, D. S., Leibrock, C. B., Rexhepaj, R., Siraskar, B., Boini, K. M., Ackermann, T. F., Föller, M., Hocher, B., Rosenblatt, K. P., Kuro-o, M., & Lang, F. (2010). Hyperaldosteronism in klotho-deficient mice. American Journal of Physiology - Renal Physiology, 299(5), F1171-F1177. https://doi.org/10.1152/ajprenal.00233.2010