联合沙格列汀治疗老年糖尿病肾病对炎症因子和单个核细胞PI3K-Akt通路的影响
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摘要
目的观察沙格列汀治疗老年糖尿病肾病对外周血TNF-α、IL-1和IL-6水平以及外周血单核细胞PI3K、Akt的磷酸化水平的影响。方法选取许昌市中心医院60例早期老年糖尿病肾病患者,比较治疗前后对照组和实验组各项指标变化。另外,沙格列汀治疗8周后观察临床各项指标包括空腹血糖、糖化血红蛋白(Hb A1 c)、24 h尿白蛋白量(24 h UPro)和血肌酐(Cr),以及血浆中TNF-α、IL-6和IL-1水平。同时,检测外周血提取的单核细胞的PI3K和Akt的磷酸化水平。结果与对照组相比,实验组外周血清空腹血糖水平显著下降(P<0.05),同时Hb A1 c显著下降(P<0.05),24 h UPro显著下降(P<0.05),血肌酐(Cr)水平显著降低(P<0.05);另外,与对照组相比,实验组患者血浆中炎症因子TNF-α、IL-6和IL-β的表达水平显著降低(P<0.05);与对照组相比,实验组的外周血提取的单核细胞中PI3K的磷酸化水平和Akt表达水平也显著升高(P<0.05)。结论沙格列汀治疗老年糖尿病肾病患者可显著降低Hb A1 c、24 h UPro和Cr,进而改善肾功能,同时可降低外周血TNF-α、IL-6和IL-1β水平,缓解外周炎症免疫反应,并显著上调外周血单核细胞的PI3K和Akt磷酸化水平。沙格列汀在改善外周血高血糖状态时,进一步恢复PI3K/Akt磷酸化活化水平,参与抑制炎症反应。
This study was designed to investigate the effects of saxagliptin on peripheral blood TNF-α, IL-1 and IL-6 levels as well as the phosphorylation levels of PI3 K-Akt in peripheral blood mononuclear cells of elderly diabetic nephropathy patients. Total of 60 cases of early senile diabetic nephropathy was recruited from Xuchang Central Hospital, and divided randomly into control and experiment groups. The clinical indices of the control group and the experimental group were compared before and after treatment. In addition, after 8 weeks of saxagliptin treatment, we observed the clinical indicators including fasting blood glucose, glycosylated hemoglobin(Hb A1 C), 24 hour urine protein(24 h UPro), serum creatinine(Cr), and the levels of TNF-α, IL-6 and IL-1β in plasma. Furthermore, PI3 K and Akt phosphorylation levels of monocytes extracted from peripheral blood were tested by Western blot. Data showed that the serum fasting blood glucose, Hb A1 c, 24 h UPro, serum creatinine(Cr)levels, and the levels of plasma TNF-α, IL-1β and IL-6 of experimental group decreased significantly,as compared with control group(P<0.05). The levels of PI3 K phosphorylation and Akt expression in monocytes the experimental group were significantly increased compared with the control group(P<0.05). Taken together,treatment of combined saxagliptin can reduce Hb A1 C, 24 h UPro, Cr, and the levels of TNF-α, IL-6 and IL-1β in peripheral blood, thus relieve the peripheral inflammatory responses in elderly patients. Meanwhile, saxagliptin also up-regulates the levels PI3 K and Akt phosphorylation of monocytes from peripheral blood. Saxagliptin improves the level of PI3 K/Akt phosphorylation and participates in the inhibition of inflammatory response by improving the peripheral blood glucose status.
This study was designed to investigate the effects of saxagliptin on peripheral blood TNF-α, IL-1 and IL-6 levels as well as the phosphorylation levels of PI3 K-Akt in peripheral blood mononuclear cells of elderly diabetic nephropathy patients. Total of 60 cases of early senile diabetic nephropathy was recruited from Xuchang Central Hospital, and divided randomly into control and experiment groups. The clinical indices of the control group and the experimental group were compared before and after treatment. In addition, after 8 weeks of saxagliptin treatment, we observed the clinical indicators including fasting blood glucose, glycosylated hemoglobin(Hb A1 C), 24 hour urine protein(24 h UPro), serum creatinine(Cr), and the levels of TNF-α, IL-6 and IL-1β in plasma. Furthermore, PI3 K and Akt phosphorylation levels of monocytes extracted from peripheral blood were tested by Western blot. Data showed that the serum fasting blood glucose, Hb A1 c, 24 h UPro, serum creatinine(Cr)levels, and the levels of plasma TNF-α, IL-1β and IL-6 of experimental group decreased significantly,as compared with control group(P<0.05). The levels of PI3 K phosphorylation and Akt expression in monocytes the experimental group were significantly increased compared with the control group(P<0.05). Taken together,treatment of combined saxagliptin can reduce Hb A1 C, 24 h UPro, Cr, and the levels of TNF-α, IL-6 and IL-1β in peripheral blood, thus relieve the peripheral inflammatory responses in elderly patients. Meanwhile, saxagliptin also up-regulates the levels PI3 K and Akt phosphorylation of monocytes from peripheral blood. Saxagliptin improves the level of PI3 K/Akt phosphorylation and participates in the inhibition of inflammatory response by improving the peripheral blood glucose status.
引文
[1]袁婷,关晓菲,卢文冉,等.Toll样受体的内源性激活在糖尿病及糖尿病肾病中的作用—TLRs表达、激活促进DM和DN的发生、发展[J].中国免疫学杂志,2015,31(8):1124-1128.
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[13]王绘,万丽丽,高玮.沙格列汀联合替米沙坦对2型糖尿病早期糖尿病肾病患者的治疗效果[J].江苏医药,2017,43(6):446-448.
[14]何笑云,欧春麟,肖艳华,等.沙格列汀对高糖诱导内皮细胞中Lnc RNA-MALAT1表达的影响[J].医学研究生学报,2016,29(9):902-905.
[15]Cooper ME.Diabetes:treating diabetic nephropathy-still an unresolved issue[J].Nat Rev Endocrinol,2012,8(9):515-516.
[16]Kocak N,Alacacioglu I,Kaynak S,et al.Comparison of vitreous and plasma levels of vascular endothelial growth factor,interleukin-6 and hepatocyte growth factor in diabetic and non-diabetic retinal detachment cases[J].Ann Ophthalmol(Skokie),2010,42:10-14.
[17]张体华,王明.糖尿病肾病患者炎症水平、免疫功能及与肾脏病变的关系[J].中国免疫学杂志,2016,32(10):1524-1526,1531.
[18]Pickup JC,Chusney GD,Thomas SM,et al.Plasma interleukin-6,tumour necrosis factor and blood cytokineproduction in type 2 diabetes[J].Life Sci,2000,67(3):291-300.
[19]Bruno G,Merletti F,Biggeri A,et al.Progression to over nephropathy in type 2 diabetes:the Casale Monferrato study[J].Diabetes Care,2003,26(7):2150-2155.
[20]Sun L,Kanwar YS.Relevance of TNF-αin the context of other inflammatory cytokines in the progression of diabetic nephropathy[J].Kidney Int,2015,88(4):662-665.
[21]Chen Y,Qian H,Zhu W,et al.Hamdy.Hepatocyte growth factor modification promotes the amelioration effects of human umbilical cord mesenchymal stem cells on rat acute kidney injury[J].Stem Cells Dev,2011,20(1):103-113.
[22]Lucas K,Maes M.Role of the Toll like receptor(TLR)radical cycle in chronic inflammation:possible treatments targeting the TLR4 pathway[J].Mol Neurobiol,2013,48(1):190-204.
[23]Vandanmagsar B,Youm YH,Ravussin A,et al.The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance[J].Nat Med,2011,17(2):179-188.
[24]Schertzer JD,Tamrakar AK,Magalh?es JG,et al.NOD1activators link innate immunity to insulin resistance[J].Diabetes,2011,60(9):2206-2215.
[25]Chen JW,Gall MA,Yokoyama H,et al.Raised serum sialic acid concentration in NIDDM patients with and without diabetic nephropathy[J].Diabetes Care,1996,19(2):130-134.
[26]Rodrguez Moran M,Guerrero Romero F.Increased levels of C-reactive protein in noncontrolled type II diabetic subjects[J].J Diabetes Complications,1999,13(4):211-215.
[27]Tousoulis D,Papageorgiou N,Androulakis E,et al.Diabetes mellitus-associated vascular impairment:novel circulating biomarkers and therapeutic approaches[J].J Am Coll Cardiol,2013,62(8):667-676.
[28]刘洁,李英,刘茂东,等.缬沙坦对高糖环境中肾小球系膜细胞megsin表达的影响[J].免疫学杂志,2012,28(6):480-484.
[29]Navarro González JF,Mora Fernández C,Muros de Fuentes M,et al.Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy[J].Nat Rev Nephrol,2011,7(6):327-40.
[30]Navarro González JF,Mora Fernández C.The role of inflammatory cytokines in diabetic nephropathy[J].J Am Soc Nephrol,2008,19(3):433-442.
[31]Guan J,Long L,Chen YQ,et al.Effects of beraprost sodium on renal function and inflammatory factors of rats with diabetic nephropathy[J].Genet Mol Res,2014,13(2):4154-4158.
[32]Eyre J,Burton JO,Saleem MA,et al.Monocyte-and endothelial-derived microparticles induce an inflammatory phenotype in human podocytes[J].Nephron Exp Nephrol,2011,119(3):e58-e66.
[33]Baud L,Fouqueray B,Philippe C,et al.Tumor necrosis factor alpha and mesangial cells[J].Kidney Int,1992,41(3):600-603.
[34]Egido J,Gomez Chiarri MG,Ortíz A,et al.Role of tumor necrosis factor-alpha in the pathogenesis of glomerular diseases[J].Kidney Int,1993,39:S59-S64.
[35]Chana RS,Martin J,Rahman EU,et al.Monocyte adhesion to mesangial matrix modulates cytokine and metalloproteinase production[J].Kidney Int,2003,63(3):889-898.
[36]Mora C,Navarro JF,Moriwaki Y,et al.Inflammation and pathogenesis of diabetic nephropathy[J].Metabolism,2004,53(2):265-267.
[37]Chen FQ,Wang J,Liu XB,et al.Levels of inflammatory cytokines in type 2 diabetes patients with different urinary albumin excretion rates and their correlation with clinical variables[J].J Diabetes Res,2013,2013:138969.
[38]徐春艳,赵林双.糖尿病肾病大鼠血清AT1-AA与肾皮质中mi RNA-155之间的相关性研究[J].免疫学杂志,2014,30(11):952-956.
[39]Noronha IL,Niemir Z,Stein H,et al.Cytokines and growth factors in renal disease[J].Nephrol Dial Transplant,1995,10(6):775-786.
[40]Yano T,Itoh Y,Matsuo M,et al.Involvement of both tumor necrosis factor-alpha-induced necrosis and p53-mediated caspase-dependent apoptosis in nephrotoxicity of cisplatin[J].Apoptosis.2007,12(10):1901-1909.
[41]Mccarthy ET,Sharma R,Sharma M,et al.TNF-αincreases albumin permeability of isolated rat glomeruli through the generation of superoxide[J].J Am Soc Nephrol,1998,9(3):433-438.
[42]Zhang Y,Feng H,Wei Z.Association between IL-18 and carotid intima-media thickness in patients with type II diabetic nephropathy[J].Med Sci Monit,2017,23:470-478.
[43]Elsherbiny NM,Al Gayyar MM.The role of IL-18 in type1 diabetic nephropathy:The problem and future treatment[J].Cytokine,2016,81:15-22.
[44]Nakamura A,Shikata K,Hiramatsu M,et al.Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes[J],Diabetes Care,2005,28(12):2890-2895.
[45]Wong CK,Ho AW,Tong PC,et al.Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy[J].Clin Exp Immunol,2007,149(1):123-131.
[46]Okamura H,Tsutsui H,Komatsu T,et al.Cloning of a new cytokine that induces IFN-gamma production by T cells[J].Nature,1995,378(6552):88-91.
[47]Schwarz M,Wahl M,Resch K,et al.IFNgamma induces functional chemokine receptor expression in human mesangial cells[J],Clin Exp Immunol,2002,128(2):285-294.
[2]Afkarian M,Zolnick LR,Hall YN,et al.Clinical manifestations of kidney disease among US adults with diabetes 1988-2014[J].JAMA,2016,316(6):602-610.
[3]Guyton AC,Hall JE.Guyton and Hall textbook of medical physiology[M].1stediton.Philadelphia:Elsevier Saunders,2006:310.
[4]Westall GP,Binder J,Kotsimbos T,et al.Nodular glomerulosclerosis in cystic fibrosis mimics diabetic nephropathy[J].Nephron Clin Pract,2004,96(3):c70-c75.
[5]Mora Fernández C,Domínguez Pimentel V,de Fuentes MM,et al.Diabetic kidney disease:from physiology to therapeutics[J].J Physiol,2014,592(18):3997–4012.
[6]Ding Y,Choi ME.Autophagy in diabetic nephropathy[J].J Endocrinol,2015,224(1):15-30.
[7]Xu G,Qin Q,Yang M,et al.Heparanase-driven inflammation from the AGEs-stimulated macrophages changes the functions of glomerular endothelial cells[J].Diabetes Res Clin Pract,2017,124:30-40.
[8]Horita S,Nakamura M,Suzuki M.Selective Insulin Resistance in the Kidney[J].Biomed Res Int.2016,414(6865):799–806.
[9]Gong W,Yu J,Wang Q,et al.Estrogen-related receptor(ERR)γprotects against puromycin aminonucleosideinduced podocyte apoptosis by targeting PI3K/Akt signaling[J].Int J Biochem Cell Biol,2016,78:75-86.
[10]Verschoor CP,Johnstone J,Loeb M,et al.Antipneumococcal deficits of monocyte-derived macrophages from the advanced-age,frail elderly and related impairments in PI3K-AKT signaling[J].Hum Immunol,2014,75:1192-1196.
[11]林凤平,李彩艳.沙格列汀对糖尿病肾病尿微量白蛋白的影响[J].湖北科技学院学报(医学版),2016,30(1):13-14.
[12]叶夏云,赵金英,赵阳.沙格列汀治疗糖尿病肾病的疗效观察[J].安徽医药,2017,21(11):2074-2076.
[13]王绘,万丽丽,高玮.沙格列汀联合替米沙坦对2型糖尿病早期糖尿病肾病患者的治疗效果[J].江苏医药,2017,43(6):446-448.
[14]何笑云,欧春麟,肖艳华,等.沙格列汀对高糖诱导内皮细胞中Lnc RNA-MALAT1表达的影响[J].医学研究生学报,2016,29(9):902-905.
[15]Cooper ME.Diabetes:treating diabetic nephropathy-still an unresolved issue[J].Nat Rev Endocrinol,2012,8(9):515-516.
[16]Kocak N,Alacacioglu I,Kaynak S,et al.Comparison of vitreous and plasma levels of vascular endothelial growth factor,interleukin-6 and hepatocyte growth factor in diabetic and non-diabetic retinal detachment cases[J].Ann Ophthalmol(Skokie),2010,42:10-14.
[17]张体华,王明.糖尿病肾病患者炎症水平、免疫功能及与肾脏病变的关系[J].中国免疫学杂志,2016,32(10):1524-1526,1531.
[18]Pickup JC,Chusney GD,Thomas SM,et al.Plasma interleukin-6,tumour necrosis factor and blood cytokineproduction in type 2 diabetes[J].Life Sci,2000,67(3):291-300.
[19]Bruno G,Merletti F,Biggeri A,et al.Progression to over nephropathy in type 2 diabetes:the Casale Monferrato study[J].Diabetes Care,2003,26(7):2150-2155.
[20]Sun L,Kanwar YS.Relevance of TNF-αin the context of other inflammatory cytokines in the progression of diabetic nephropathy[J].Kidney Int,2015,88(4):662-665.
[21]Chen Y,Qian H,Zhu W,et al.Hamdy.Hepatocyte growth factor modification promotes the amelioration effects of human umbilical cord mesenchymal stem cells on rat acute kidney injury[J].Stem Cells Dev,2011,20(1):103-113.
[22]Lucas K,Maes M.Role of the Toll like receptor(TLR)radical cycle in chronic inflammation:possible treatments targeting the TLR4 pathway[J].Mol Neurobiol,2013,48(1):190-204.
[23]Vandanmagsar B,Youm YH,Ravussin A,et al.The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance[J].Nat Med,2011,17(2):179-188.
[24]Schertzer JD,Tamrakar AK,Magalh?es JG,et al.NOD1activators link innate immunity to insulin resistance[J].Diabetes,2011,60(9):2206-2215.
[25]Chen JW,Gall MA,Yokoyama H,et al.Raised serum sialic acid concentration in NIDDM patients with and without diabetic nephropathy[J].Diabetes Care,1996,19(2):130-134.
[26]Rodrguez Moran M,Guerrero Romero F.Increased levels of C-reactive protein in noncontrolled type II diabetic subjects[J].J Diabetes Complications,1999,13(4):211-215.
[27]Tousoulis D,Papageorgiou N,Androulakis E,et al.Diabetes mellitus-associated vascular impairment:novel circulating biomarkers and therapeutic approaches[J].J Am Coll Cardiol,2013,62(8):667-676.
[28]刘洁,李英,刘茂东,等.缬沙坦对高糖环境中肾小球系膜细胞megsin表达的影响[J].免疫学杂志,2012,28(6):480-484.
[29]Navarro González JF,Mora Fernández C,Muros de Fuentes M,et al.Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy[J].Nat Rev Nephrol,2011,7(6):327-40.
[30]Navarro González JF,Mora Fernández C.The role of inflammatory cytokines in diabetic nephropathy[J].J Am Soc Nephrol,2008,19(3):433-442.
[31]Guan J,Long L,Chen YQ,et al.Effects of beraprost sodium on renal function and inflammatory factors of rats with diabetic nephropathy[J].Genet Mol Res,2014,13(2):4154-4158.
[32]Eyre J,Burton JO,Saleem MA,et al.Monocyte-and endothelial-derived microparticles induce an inflammatory phenotype in human podocytes[J].Nephron Exp Nephrol,2011,119(3):e58-e66.
[33]Baud L,Fouqueray B,Philippe C,et al.Tumor necrosis factor alpha and mesangial cells[J].Kidney Int,1992,41(3):600-603.
[34]Egido J,Gomez Chiarri MG,Ortíz A,et al.Role of tumor necrosis factor-alpha in the pathogenesis of glomerular diseases[J].Kidney Int,1993,39:S59-S64.
[35]Chana RS,Martin J,Rahman EU,et al.Monocyte adhesion to mesangial matrix modulates cytokine and metalloproteinase production[J].Kidney Int,2003,63(3):889-898.
[36]Mora C,Navarro JF,Moriwaki Y,et al.Inflammation and pathogenesis of diabetic nephropathy[J].Metabolism,2004,53(2):265-267.
[37]Chen FQ,Wang J,Liu XB,et al.Levels of inflammatory cytokines in type 2 diabetes patients with different urinary albumin excretion rates and their correlation with clinical variables[J].J Diabetes Res,2013,2013:138969.
[38]徐春艳,赵林双.糖尿病肾病大鼠血清AT1-AA与肾皮质中mi RNA-155之间的相关性研究[J].免疫学杂志,2014,30(11):952-956.
[39]Noronha IL,Niemir Z,Stein H,et al.Cytokines and growth factors in renal disease[J].Nephrol Dial Transplant,1995,10(6):775-786.
[40]Yano T,Itoh Y,Matsuo M,et al.Involvement of both tumor necrosis factor-alpha-induced necrosis and p53-mediated caspase-dependent apoptosis in nephrotoxicity of cisplatin[J].Apoptosis.2007,12(10):1901-1909.
[41]Mccarthy ET,Sharma R,Sharma M,et al.TNF-αincreases albumin permeability of isolated rat glomeruli through the generation of superoxide[J].J Am Soc Nephrol,1998,9(3):433-438.
[42]Zhang Y,Feng H,Wei Z.Association between IL-18 and carotid intima-media thickness in patients with type II diabetic nephropathy[J].Med Sci Monit,2017,23:470-478.
[43]Elsherbiny NM,Al Gayyar MM.The role of IL-18 in type1 diabetic nephropathy:The problem and future treatment[J].Cytokine,2016,81:15-22.
[44]Nakamura A,Shikata K,Hiramatsu M,et al.Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes[J],Diabetes Care,2005,28(12):2890-2895.
[45]Wong CK,Ho AW,Tong PC,et al.Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy[J].Clin Exp Immunol,2007,149(1):123-131.
[46]Okamura H,Tsutsui H,Komatsu T,et al.Cloning of a new cytokine that induces IFN-gamma production by T cells[J].Nature,1995,378(6552):88-91.
[47]Schwarz M,Wahl M,Resch K,et al.IFNgamma induces functional chemokine receptor expression in human mesangial cells[J],Clin Exp Immunol,2002,128(2):285-294.