title: Regulatory T cells improve nephrocalcinosis but not dystrophic cardiac calcinosis in DBA/2 mice.
abstract: Nephrocalcinosis is characterized by aberrant deposition of calcium in the kidneys and is seen in phosphate nephropathy, primary hyperparathyroidism, and distal renal tubular acidosis. To further evaluate the specific pathophysiologic role of T cells in ectopic calcification, we used DBA/2 mice that are prone to develop nephrocalcinosis and dystrophic cardiac calcinosis. Female DBA/2 mice were depleted of T cells (n = 10) or regulatory T cells (Tregs) (n = 15) using either an anti-CD3ɛ or an anti-CD25 monoclonal antibody and compared with isotype-treated controls (n = 9; n = 15), respectively. After this immunomodulation, the DBA/2 mice were given a high-phosphate diet for 9 days and the degree of calcification was assessed by microcomputed tomography. Successful depletion was confirmed by flow cytometry of splenocytes. In DBA/2 mice, the high-phosphate diet induced a phenotype of nephrocalcinosis and dystrophic cardiac calcinosis. T-cell depletion significantly increased renal calcification in microcomputed tomography (P = 0.022). Concordantly, Treg depletion significantly deteriorated acute phosphate nephropathy (P = 0.039) and was associated with a significantly increased mortality rate (P = 0.004). Immunomodulation had no impact on the amount of cardiac calcification. Semiquantitative histopathologic evaluations with Alizarin Red staining independently confirmed the respective radiologic measurements. In summary, our data suggest a pivotal role of T cells, particularly Tregs, in the progression of nephrocalcinosis and emphasize the fact that inflammation deteriorates the outcome in acute phosphate nephropathy.
authors.affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Kirsch
authors.forename: Nicole
authors.initials: N
authors.lastname: Smaczny
authors.forename: Viktoria
authors.initials: V
authors.lastname: Riegelbauer
authors.forename: Simon
authors.initials: S
authors.lastname: Sedej
authors.forename: Alexander
authors.initials: A
authors.lastname: Hofmeister
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stojakovic
authors.forename: Walter
authors.initials: W
authors.lastname: Goessler
authors.forename: Marianne
authors.initials: M
authors.lastname: Brodmann
authors.forename: Ernst
authors.initials: E
authors.lastname: Pilger
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Rosenkranz
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eller
authors.forename: Philipp
authors.initials: P
authors.lastname: Eller
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D009202:Cardiomyopathies / Q000139:chemically induced / Q000276:immunology*; D017886:Durapatite / Q000378:metabolism; D005260:Female; D008231:Lymphopenia / Q000139:chemically induced / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D009397:Nephrocalcinosis / Q000139:chemically induced / Q000276:immunology*; D010641:Phenotype; D010710:Phosphates / Q000633:toxicity; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D061205:Vascular Calcification / Q000139:chemically induced / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D010710:Phosphates; D017886:Durapatite