Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet

Kidney Int. 2012 Dec;82(12):1261-70. doi: 10.1038/ki.2012.322. Epub 2012 Aug 29.

Abstract

Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for 3 weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high-phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation; however, the expression of the anticalcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Aorta / drug effects*
  • Aorta / metabolism
  • Aorta / pathology
  • Aortic Diseases / etiology
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Calcitriol / administration & dosage
  • Calcitriol / pharmacology*
  • Calcium / blood
  • Cells, Cultured
  • Diet*
  • Disease Models, Animal
  • Elastin / metabolism
  • Ergocalciferols / administration & dosage
  • Ergocalciferols / pharmacology*
  • Female
  • Fibroblast Growth Factors / blood
  • Glucuronidase / blood
  • Glucuronidase / metabolism*
  • Glucuronidase / urine
  • Injections, Intraperitoneal
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / metabolism
  • Osteopontin / metabolism*
  • Parathyroid Hormone / blood
  • Phosphates* / blood
  • Receptors, Calcitriol / agonists*
  • Receptors, Calcitriol / metabolism
  • Renal Insufficiency, Chronic / drug therapy*
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / metabolism
  • Time Factors
  • Up-Regulation
  • Vascular Calcification / etiology
  • Vascular Calcification / metabolism
  • Vascular Calcification / pathology
  • Vascular Calcification / prevention & control*

Substances

  • Ergocalciferols
  • Parathyroid Hormone
  • Phosphates
  • Receptors, Calcitriol
  • Spp1 protein, mouse
  • Osteopontin
  • Fibroblast Growth Factors
  • paricalcitol
  • fibroblast growth factor 23
  • Elastin
  • Glucuronidase
  • klotho protein
  • Calcitriol
  • Calcium