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 Ca(2+) 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, 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(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, Ca(2+), 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 Ca(2+)-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.
Fischer
Stephanie S
SS
Physiologisches Institut der Universität Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
Kempe
Daniela S
DS
Leibrock
Christina B
CB
Rexhepaj
Rexhep
R
Siraskar
Balasaheb
B
Boini
Krishna M
KM
Ackermann
Teresa F
TF
Föller
Michael
M
Hocher
Berthold
B
Rosenblatt
Kevin P
KP
Kuro-O
Makoto
M
Lang
Florian
F
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001774:Blood Chemical Analysis; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002117:Calcitriol / Q000378:metabolism; D015194:Diffusion Chambers, Culture; D004573:Electrolytes / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase / Q000235:genetics* / Q000502:physiology*; D006929:Hyperaldosteronism / Q000235:genetics* / Q000378:metabolism; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000097:blood; D010953:Plasma Volume / Q000502:physiology; D013534:Survival; D014667:Vasopressins / Q000097:blood
D004573:Electrolytes; C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D014667:Vasopressins; D000450:Aldosterone; D000089703:Fibroblast Growth Factor-23; D000324:Adrenocorticotropic Hormone; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol