Faculty of Pharmacy, Department of Pharmacology, Ege University, Izmir, Turkey.
J Surg Res. 2013 Jun 1;182(1):176-84. doi: 10.1016/j.jss.2012.08.020. Epub 2012 Aug 25.
Acute renal failure due to renal ischemia/reperfusion (IR) injury is a significant clinical problem in cardiovascular surgery. Reactive oxygen species and inflammation play essential roles in the pathophysiology of IR injury. Matrix metalloproteinases (MMPs) are enzymes that play important roles in inflammation and mediate extracellular matrix degradation. It is known that peroxisome proliferator-activated receptor-γ agonists have antiinflammatory and antioxidant effects. In the present study, we aimed to investigate the effects of pioglitazone, a synthetic peroxisome proliferator-activated receptor-γ agonist, on MMPs and oxidative stress in a renal IR injury model in rats.
Male Wistar albino rats were divided into three groups: control (n = 7), placebo (n = 7; saline/p.o.), and pioglitazone (n = 7; 5 mg/kg/day/p.o.). In the control group, a right nephrectomy was conducted without left renal IR injury. In the placebo and pioglitazone groups, pretreatments were started 3 d before operation. In both groups, left renal pedicles were clamped for 60 min and then reperfused for 60 min. Paraffinized renal sections were evaluated histopathologically. Furthermore, expressions of MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2, superoxide dismutase 1 (SOD1), and p47-phox/p67-phox subunits of NADPH oxidase were determined by immunostaining and scoring.
In the placebo group, renal IR injury induced diffuse tubular necrosis and intense acute inflammation, but pioglitazone inhibited these effects. MMP-2, MMP-9, and TIMP-2 expression increased in the placebo group. However, while MMP-2 and -9 expression decreased, TIMP-2 expression did not change in the pioglitazone group. p47-phox/p67-phox expression increased in the placebo group, but SOD1 expression did not change. Pioglitazone diminished p47-phox/p67-phox expression, whereas it enhanced SOD1 expression.
Our results suggest that pioglitazone might be helpful to reduce renal IR injury because of its antiinflammatory and antioxidant effects.
由于肾缺血/再灌注（IR）损伤导致的急性肾衰竭是心血管手术中的一个重要临床问题。活性氧和炎症在 IR 损伤的病理生理学中起关键作用。基质金属蛋白酶（MMPs）是在炎症中起重要作用并介导细胞外基质降解的酶。已知过氧化物酶体增殖物激活受体-γ 激动剂具有抗炎和抗氧化作用。在本研究中，我们旨在研究吡格列酮（一种合成的过氧化物酶体增殖物激活受体-γ 激动剂）对大鼠肾 IR 损伤模型中 MMPs 和氧化应激的影响。
雄性 Wistar 白化大鼠分为三组：对照组（n = 7，行右肾切除术但不进行左肾 IR 损伤）、安慰剂组（n = 7，给予生理盐水/口服）和吡格列酮组（n = 7，给予 5 mg/kg/天/口服）。在对照组中，左肾蒂夹闭 60 分钟，然后再灌注 60 分钟。对石蜡包埋的肾切片进行组织病理学评估。此外，通过免疫染色和评分来确定 MMP-2、MMP-9、金属蛋白酶组织抑制剂（TIMP）-2、超氧化物歧化酶 1（SOD1）和 NADPH 氧化酶的 p47-phox/p67-phox 亚基的表达。
在安慰剂组中，肾 IR 损伤导致弥漫性肾小管坏死和强烈的急性炎症，但吡格列酮抑制了这些作用。MMP-2、MMP-9 和 TIMP-2 的表达在安慰剂组中增加。然而，尽管 MMP-2 和 -9 的表达减少，但吡格列酮组中 TIMP-2 的表达没有改变。p47-phox/p67-phox 的表达在安慰剂组中增加，而 SOD1 的表达没有改变。吡格列酮降低了 p47-phox/p67-phox 的表达，而增强了 SOD1 的表达。
我们的结果表明，吡格列酮可能通过其抗炎和抗氧化作用有助于减轻肾 IR 损伤。
