Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice.
The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA.
['Chiasson|Valorie L|VL|', 'Bounds|Kelsey R|KR|', 'Chatterjee|Piyali|P|', 'Manandhar|Lochana|L|', 'Pakanati|Abhinandan R|AR|', 'Hernandez|Marcos|M|', 'Aziz|Bilal|B|', 'Mitchell|Brett M|BM|']
D000818:Animals D001685:Biological Factors D001794:Blood Pressure D001808:Blood Vessels D065095:Calcineurin Inhibitors D016572:Cyclosporine D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D006973:Hypertension D000067596:Interleukin-33 D007668:Kidney D051379:Mice D000072737:Myeloid-Derived Suppressor Cells D051437:Renal Insufficiency
myeloid-derived suppressor cells cyclosporine hypertension calcineurin myeloid cells