Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation
Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation
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DOI：
10.1152/ajprenal.00288.2005
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发表时间：
2007-04-01
影响因子：
4.2
通讯作者：
Makino, Hirofumi
中科院分区：
文献类型：
--
作者：
Ohga, Sakiko;Shikata, Kenichi;Makino, Hirofumi
噻唑烷二酮(TZD)是过氧化物酶体增殖物激活受体-γ(PPAR-γ)的配体，其抗炎作用不依赖于胰岛素增敏作用。在目前的研究中，我们验证了TZD通过调节炎症过程来预防糖尿病肾病进展的假设。5周龄SD大鼠分为3组：1)非糖尿病对照组(Non-DM)，2)糖尿病大鼠(DM)，3)吡格列酮治疗(DM+Pio)糖尿病大鼠。链脲佐菌素(STZ)诱导糖尿病大鼠模型。DM+Pio组在糖尿病诱导后给予0.0002%吡格列酮混合饲料治疗8wk。糖尿病大鼠血糖和糖化血红蛋白升高，但吡格列酮治疗后血糖和糖化血红蛋白无变化。吡格列酮可减少糖尿病大鼠的尿白蛋白排泄和肾小球肥大，抑制转化生长因子-β、IV型胶原和ICAM-1的表达，并抑制巨噬细胞在糖尿病大鼠肾脏的浸润。糖尿病大鼠肾组织核因子-kappaB活性升高，而吡格列酮使其活性降低。PPAR-γ在糖尿病肾小球内皮细胞和培养的肾小球内皮细胞均有表达。高糖环境下肾小球内皮细胞ICAM-1表达增加，核因子-kappaB活化。这些变化可被吡格列酮、西格列酮和核因子-kappa B的抑制剂吡咯烷二硫代氨基甲酸酯所减弱，但在PPAR-kappa B拮抗剂GW9662存在下，吡格列酮不表现出这种变化。我们的结果提示，吡格列酮的预防作用可能与其抗炎作用有关，包括抑制核因子-kappaB的激活，抑制ICAM-1的表达，以及抑制巨噬细胞在糖尿病肾脏的浸润。
Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), exerts anti-inflammatory effects independently of the insulin-sensitizing effect. In the present study, we tested the hypothesis that TZD prevents the progression of diabetic nephropathy by modulating the inflammatory process. Five-week-old Sprague-Dawley rats were divided into three groups: 1) nondiabetic control rats (non-DM), 2) diabetic rats (DM), and 3) diabetic rats treated with pioglitazone (DM + pio). Diabetes was induced by injection with streptozotocin (STZ). The DM + pio group received 0.0002% pioglitazone mixed in chow for 8 wk after induction of diabetes. Blood glucose and HbA1c were elevated in diabetic rats but did not change by treatment with pioglitazone. Pioglitazone reduced urinary albumin excretion and glomerular hypertrophy, suppressed the expression of transforming growth factor (TGF)-beta, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-kappa B activity was increased in diabetic rats and reduced by pioglitazone. PPAR-gamma was expressed in glomerular endothelial cells in the diabetic kidney and in cultured glomerular endothelial cells. High-glucose conditions increased the expression of ICAM-1 and the activation of NF-kappa B in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-kappa B. However, pioglitazone did not show the changes in the presence of PPAR-kappa B antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-kappa B activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney.