Chang Po-Chiao, Chen Tso-Hsiao, Chang Chun-Jen, Hou Chun-Cheng, Chan Paul, Lee Horng-Mo
Graduate Institute of Biomedical Technology, Taipei Medical University, Taipei, Taiwan.
Kidney Int. 2004 May;65(5):1664-75. doi: 10.1111/j.1523-1755.2004.00602.x.
Advanced glycosylation end products (AGEs) accumulation in tissue has been implicated in diabetic related complications, including diabetic nephropathy. Activation of peroxisome proliferator activated receptor-gamma (PPAR-gamma) ameliorates diabetic nephropathy.
In the present study, we investigated the effects of AGEs on inducible nitric oxide synthase (iNOS) expression and nitric oxide production, and the effects of rosiglitazone, an activator of PPAR-gamma, on AGE-induced iNOS expression and nitrite release in glomerular mesangial cells.
AGEs caused a dose- and time-dependent increase of iNOS induction and nitrite accumulation in mesangial cells. A protein tyrosine kinase inhibitor (genistein), or a p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580) suppressed AGE-induced iNOS expression and nitrite release from mesangial cells. Addition of bovine serum albumin (BSA)-AGEs to mesangial cells increased p38 MAPK activities. Activation of PPAR-gamma by rosiglitazone inhibited AGE-induced iNOS expression, nitrite release, and p38 MAPK activation in mesangial cells. AGE-stimulated nitrite release was attenuated by pretreatment with anti-tumor necrosis factor-alpha (TNF-alpha) and anti-transforming growth factor-beta (TGF-beta) antibodies. AGE-induced iNOS expression was inhibited by treatment with a nuclear factor-kappaB (NF-kappaB) inhibitor, pyrrolidone dithiocarbamate. Addition of BSA-AGEs to mesangial cells stimulated p65 NF-kappaB translocation from the cytosol to the nucleus.
These data suggest that cytokine release, NF-kappaB and p38 MAPK-dependent pathways may play a role in AGE-induced iNOS expression and subsequent nitric oxide production in mesangial cells. Rosiglitazone may prevent AGE-induced iNOS expression by interfering with p38 MAPK activity.
组织中晚期糖基化终末产物（AGEs）的积累与糖尿病相关并发症有关，包括糖尿病肾病。过氧化物酶体增殖物激活受体γ（PPAR-γ）的激活可改善糖尿病肾病。
在本研究中，我们研究了AGEs对诱导型一氧化氮合酶（iNOS）表达和一氧化氮产生的影响，以及PPAR-γ激活剂罗格列酮对AGE诱导的肾小球系膜细胞中iNOS表达和亚硝酸盐释放的影响。
AGEs导致系膜细胞中iNOS诱导和亚硝酸盐积累呈剂量和时间依赖性增加。蛋白酪氨酸激酶抑制剂（染料木黄酮）或p38丝裂原活化蛋白激酶（MAPK）抑制剂（SB203580）可抑制AGE诱导的系膜细胞中iNOS表达和亚硝酸盐释放。向系膜细胞中添加牛血清白蛋白（BSA）-AGEs可增加p38 MAPK活性。罗格列酮激活PPAR-γ可抑制系膜细胞中AGE诱导的iNOS表达、亚硝酸盐释放和p38 MAPK激活。用抗肿瘤坏死因子-α（TNF-α）和抗转化生长因子-β（TGF-β）抗体预处理可减弱AGE刺激的亚硝酸盐释放。用核因子-κB（NF-κB）抑制剂吡咯烷二硫代氨基甲酸盐处理可抑制AGE诱导的iNOS表达。向系膜细胞中添加BSA-AGEs可刺激p65 NF-κB从细胞质转位至细胞核。
这些数据表明，细胞因子释放、NF-κB和p38 MAPK依赖性途径可能在AGE诱导的系膜细胞中iNOS表达及随后的一氧化氮产生中起作用。罗格列酮可能通过干扰p38 MAPK活性来预防AGE诱导的iNOS表达。
