title: Bicarbonate-sensitive calcification and lifespan of klotho-deficient mice.
abstract: Klotho, a protein counteracting aging, is a powerful inhibitor of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] formation and regulator of mineral metabolism. In klotho hypomorphic (kl/kl) mice, excessive 1,25(OH)2D3 formation leads to hypercalcemia, hyperphosphatemia and vascular calcification, severe growth deficits, accelerated aging and early death. Kl/kl mice further suffer from extracellular volume depletion and hypotension, leading to the stimulation of antidiuretic hormone and aldosterone release. A vitamin D-deficient diet, restriction of dietary phosphate, inhibition of mineralocorticoid receptors with spironolactone, and dietary NaCl all extend the lifespan of kl/kl mice. Kl/kl mice suffer from acidosis. The present study explored whether replacement of tap drinking water by 150 mM NaHCO3 affects the growth, tissue calcification, and lifespan of kl/kl mice. As a result, NaHCO3 administration to kl/kl mice did not reverse the growth deficit but substantially decreased tissue calcification and significantly increased the average lifespan from 78 to 127 days. NaHCO3 did not significantly affect plasma concentrations of 1,25(OH)2D3 and Ca(2+) but significantly decreased plasma phosphate concentration and plasma aldosterone concentration. The present study reveals a novel effect of bicarbonate, i.e., a favorable influence on vascular calcification and early death of klotho-deficient mice.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany;
authors.forename: Christina B
authors.initials: CB
authors.lastname: Leibrock
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany;
authors.forename: Jakob
authors.initials: J
authors.lastname: Voelkl
authors.affiliation: Department of Pathology, University of Tübingen, Tübingen, Germany; and.
authors.forename: Ursula
authors.initials: U
authors.lastname: Kohlhofer
authors.affiliation: Department of Pathology, University of Tübingen, Tübingen, Germany; and.
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.affiliation: Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany; florian.lang@uni-tuebingen.de.
authors.forename: Florian
authors.identifier: http://orcid.org/0000-0003-2962-1540
authors.initials: F
authors.lastname: Lang
mesh_terms: D000138:Acidosis / Q000097:blood / Q000235:genetics; D000450:Aldosterone / Q000097:blood; D000818:Animals; D002114:Calcinosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood; D005838:Genotype; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics; D006929:Hyperaldosteronism / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D054559:Hyperphosphatemia / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D007408:Intestinal Absorption / Q000187:drug effects; D000090265:Klotho Proteins; D008136:Longevity; D018345:Mice, Knockout; D010641:Phenotype; D010710:Phosphates / Q000097:blood; D065667:Renal Elimination / Q000187:drug effects; D017693:Sodium Bicarbonate / Q000494:pharmacology*; D013997:Time Factors; D061205:Vascular Calcification / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control
chemical_list: D010710:Phosphates; D000450:Aldosterone; D017693:Sodium Bicarbonate; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol; D002118:Calcium
keywords: 1,25(OH)2D3; aldosterone; alkalosis; antidiuretic hormone; calcium; phosphate