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Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice.
- Source :
-
Hypertension (Dallas, Tex. : 1979) [Hypertension] 2017 Jul; Vol. 70 (1), pp. 183-191. Date of Electronic Publication: 2017 Jun 05. - Publication Year :
- 2017
-
Abstract
- The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17-producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4 <superscript>+</superscript> /FoxP3 <superscript>+</superscript> regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17-neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice.<br /> (© 2017 American Heart Association, Inc.)
- Subjects :
- Animals
Calcineurin Inhibitors pharmacology
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
Endothelium, Vascular pathology
Glomerular Mesangium drug effects
Glomerular Mesangium metabolism
Glomerular Mesangium pathology
Immunosuppressive Agents pharmacology
Inflammation metabolism
Inflammation pathology
Mice
Signal Transduction drug effects
Cyclosporine pharmacology
Drug-Related Side Effects and Adverse Reactions metabolism
Drug-Related Side Effects and Adverse Reactions pathology
Drug-Related Side Effects and Adverse Reactions prevention & control
Hypertension metabolism
Hypertension prevention & control
Interleukin-17 metabolism
Renal Insufficiency metabolism
Renal Insufficiency prevention & control
T-Lymphocytes, Regulatory physiology
Tacrolimus pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4563
- Volume :
- 70
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Hypertension (Dallas, Tex. : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 28584011
- Full Text :
- https://doi.org/10.1161/HYPERTENSIONAHA.117.09374