Chiasson Valorie L, Bounds Kelsey R, Chatterjee Piyali, Manandhar Lochana, Pakanati Abhinandan R, Hernandez Marcos, Aziz Bilal, Mitchell Brett M
From the Department of Internal Medicine (V.L.C., K.R.B., P.C., L.M., A.R.P., M.H., B.A., B.M.M.) and Department of Medical Physiology (B.M.M.), Texas A&M University Health Science Center College of Medicine/Baylor Scott & White Health, Temple.
Hypertension. 2018 Jan;71(1):199-207. doi: 10.1161/HYPERTENSIONAHA.117.10306. Epub 2017 Nov 13.
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.
钙调神经磷酸酶抑制剂环孢素A（CsA）可抑制免疫系统，但会引发高血压、血管功能障碍和肾损伤。CsA会减少调节性T细胞，这有助于高血压的发展。然而，CsA对另一个重要的调节性免疫细胞亚群——髓系来源的抑制细胞（MDSCs）的影响尚不清楚。我们推测，增加MDSCs会改善CsA诱导的高血压以及血管和肾损伤及功能障碍，并且CsA会减少小鼠体内的MDSCs。每日进行白细胞介素-33治疗可增加MDSC水平，完全预防了CsA诱导的高血压以及血管和肾毒性。在高血压形成后，将对照小鼠的MDSCs过继转移到经CsA处理的小鼠体内，可剂量依赖性地降低血压以及血管和肾小球损伤。对从对照小鼠分离的主动脉和肾脏进行24小时的CsA处理，分别降低了舒张反应并增加了炎症，而MDSCs的存在可预防这些影响。MDSCs还可预防CsA诱导的微血管和肾小球内皮细胞中纤连蛋白的增加。最后，CsA通过抑制钙调神经磷酸酶并阻止细胞增殖，剂量依赖性地减少了MDSCs的数量，因为其他直接的钙调神经磷酸酶信号通路抑制剂也具有相同的剂量依赖性效应。这些数据表明，增加MDSCs可降低CsA引起的心血管和肾毒性以及高血压。
