Hyperaldosteronism in klotho-deficient mice

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)₂D ₃ in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span.