1. Department of Nephrology, Center of Nephrology, Medical School of Xi'an Jiaotong University, Xi'an 710061, China;
2. Department of Cardiovascular Medicine, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710061, China;
3. Key Laboratory of Ministry of Education for Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an 710061, China
AIM: To investigate the effects of pioglitazone on the quantity and function-related factors of regulatory and effector T cells (Treg and Teff ) of uremic apolipoprotein E knockout mice in vitro with or without the stimulation of atherosclerotic plaque-specific antigen oxidized low-density lipoprotein (oxLDL). METHODS: Uremic apolipoprotein E knockout mouse model was established by 2-step surgical procedure. After intervention with different concentrations (2 μmol/L and 20 μmol/L) of pioglitazone and PPARγ antagonist GW9662 (5 μmol/L) on splenocytes of uremic mice for 12 h in the presence or absence of oxLDL (2 mg/L), the levels of CD4+ CD25+ Foxp3+ Treg and IFNγ+ CD4+ Teff were determined by flow cytometry. The mRNA expressions of Foxp3 and IFNγ was detected by real-time fluorescent quantitative PCR. RESULTS: In vitro, oxLDL induced a Treg/Teff imbalance in splenocytes from the uremic mice. Pioglitazone upregulated the level of Treg and mRNA expression of Foxp3 in the presence of oxLDL, which was not antagonized by GW9662. Meanwhile, pioglitazone downregulated the level of Teff and mRNA expression of IFNγ in the presence or absence of oxLDL, which was reversed by GW9662. CONCLUSION: oxLDL induces a Treg/Teff imbalance in uremic apolipoprotein E knockout mice. Pioglitazone modulates the Treg/Teff imbalance probably through PPARγ-independent and-dependent mechanisms.
Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemio-logy, mechanisms, and prevention[J]. Lancet, 2013, 382(9889):339-352.
[2]
Fredman G, Spite M. Recent advances in the role of immunity in atherosclerosis[J]. Circ Res, 2013, 113(12):e111-e114.
[3]
Tse K, Tse H, Sidney J, et al. T cells in atherosclerosis[J]. Int Immunol, 2013, 25(11):615-622.
[4]
Zhang J, Hua G, Zhang X, et al. Regulatory T cells/T-helper cell 17 functional imbalance in uraemic patients on maintenance haemodialysis: a pivotal link between microinflammation and adverse cardiovascular events[J]. Nephrology (Carlton), 2010, 15(1):33-41.
Nikolov IG, Joki N, Nguyen-Khoa T,et al. Lanthanum carbonate, like sevelamer-HCl, retards the progression of vascular calcification and atherosclerosis in uremic apolipoprotein E-deficient mice[J]. Nephrol Dial Transplant, 2012, 27(2):505-513.
[7]
Mor A, Planer D, Luboshits G, et al. Role of naturally occurring CD4+CD25+ regulatory T cells in experimental atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2007, 27(4):893-900.
[8]
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method[J]. Methods,2001, 25(4):402-408.
[9]
Lindner A, Charra B, Sherrard DJ, et al. Accelerated atherosclerosis in prolonged maintenance hemodialysis[J]. N Engl J Med, 1974, 290(13):697-701.
[10]
Grant CR, Liberal R, Mieli-Vergani G, et al. Regulatory T-cells in autoimmune diseases: challenges, controversies and-yet-unanswered questions[J]. Autoimmun Rev, 2015, 14(2):105-116.
[11]
Rao DN, Naqvi RA. FoxP3: a key player in T regulatory biology[J]. Indian J Clin Biochem, 2011, 26(1):1-2.
Klingenberg R, Gerdes N, Badeau RM, et al. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis[J]. J Clin Invest, 2013, 123(3):1323-1334.
[14]
Li Q, Wang Y, Wang Y, et al. Treg/Th17 ratio acts as a novel indicator for acute coronary syndrome[J]. Cell Biochem Biophys, 2014, 70(2):1489-1498.
[15]
Meier P, Golshayan D, Blanc E, et al. Oxidized LDL modulates apoptosis of regulatory T cells in patients with ESRD[J]. J Am Soc Nephrol, 2009, 20(6):1368-1384.
[16]
Putri AY, Thaha M. Role of oxidative stress on chronic kidney disease progression[J]. Acta Med Indones, 2014, 46(3):244-252.
[17]
Yamasaki Y, Katakami N, Furukado S, et al. Long-term effects of pioglitazone on carotid atherosclerosis in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity[J]. J Atheroscler Thromb, 2010, 17(11):1132-1140.
