Hyperaldosteronism in Klotho-deficient mice

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 ( 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 hmD+ mice than in klotho+/+D+ mice, klotho hmD− mice, and klotho hmD−/+ mice. Plasma concentrations of 1,25(OH)2D3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho hmD+ mice than in klotho+/+D+ mice. Plasma volume was significantly smaller in klotho hmD−/+ mice, and plasma urea, Ca2+, phosphate and Na+, but not K+ concentrations were significantly higher in klotho hmD+ 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 hmD+ mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)2D3 in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span.