Department of Internal Medicine, University of Pisa, Pisa, Italy.
J Hypertens. 2011 Oct;29(10):1930-9. doi: 10.1097/HJH.0b013e32834abceb.
Persistent inflammation and oxidative stress influence the progression of diabetic nephropathy. Metalloproteinases (MMPs) participate in extracellular matrix remodeling. Statins show favorable anti-inflammatory effects in chronic kidney disease. We evaluated the effect of rosuvastatin on inflammatory and pro-fibrotic responses due to exposure to different glucose or free fatty acid (FFA) concentrations.
Human mesangial cells (HMCs) grown at 5.5 (normal glucose) or 22 mmol/l (high glucose) glucose or exposed to FFA were treated with angiotensin-II in the presence or absence of rosuvastatin. We measured MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 expression and activity, and quantified the fibrotic factors transforming growth factor-β1 (TGF-β1), fibronectin, and collagen IV.
At normal glucose, angiotensin-II induced a dose-dependent downregulation of MMP-2; rosuvastatin reversed this effect. On the contrary, TIMP-2 and MMP-9 were upregulated by angiotensin-II and downregulated by rosuvastatin; the effects on TIMP-1 were negligible. Some of the angiotensin-II effects were potentiated in the presence of high glucose and FFA; under both conditions, rosuvastatin was able to reverse these effects. MMP-2 and MMP-9 activity followed the same trend of expression, with rosuvastatin able to upregulate MMP-2 activity. The modulation of the MMP/TIMP system was paralleled by an increase in TGF-β1, fibronectin, and collagen-IV; all were reduced by rosuvastatin treatment. Silencing the MMP-2 gene confirmed its role in modulating some of these angiotensin-II effects.
Angiotensin-II induces a pro-fibrotic response in HMCs mainly via a dysregulation of the MMP-2/TIMP-2 pattern. This effect, partially amplified in the presence of high glucose and FFA, is reversed by rosuvastatin, suggesting another potential therapeutic application for this 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor.
持续的炎症和氧化应激影响糖尿病肾病的进展。金属蛋白酶（MMPs）参与细胞外基质的重塑。他汀类药物在慢性肾脏病中表现出良好的抗炎作用。我们评估了瑞舒伐他汀对不同葡萄糖或游离脂肪酸（FFA）浓度暴露下炎症和促纤维化反应的影响。
在 5.5mmol/L（正常葡萄糖）或 22mmol/L（高葡萄糖）葡萄糖或暴露于 FFA 的条件下培养人肾小球系膜细胞（HMC），并用血管紧张素-II 处理，并在存在或不存在瑞舒伐他汀的情况下进行处理。我们测量了 MMP-2、MMP-9、金属蛋白酶组织抑制剂-1（TIMP-1）和 TIMP-2 的表达和活性，并量化了纤维化因子转化生长因子-β1（TGF-β1）、纤维连接蛋白和胶原 IV。
在正常葡萄糖条件下，血管紧张素-II 诱导 MMP-2 的剂量依赖性下调；瑞舒伐他汀逆转了这种作用。相反，TIMP-2 和 MMP-9 被血管紧张素-II 上调，被瑞舒伐他汀下调；对 TIMP-1 的影响可以忽略不计。在高葡萄糖和 FFA 的存在下，一些血管紧张素-II 的作用被增强；在这两种情况下，瑞舒伐他汀都能够逆转这些作用。MMP-2 和 MMP-9 的活性与表达呈相同趋势，瑞舒伐他汀能够上调 MMP-2 的活性。MMP/TIMP 系统的调节伴随着 TGF-β1、纤维连接蛋白和胶原 IV 的增加；所有这些都被瑞舒伐他汀治疗所减少。沉默 MMP-2 基因证实了其在调节一些血管紧张素-II 作用中的作用。
血管紧张素-II 主要通过 MMP-2/TIMP-2 模式的失调诱导 HMC 产生促纤维化反应。这种作用在高葡萄糖和 FFA 的存在下部分放大，被瑞舒伐他汀逆转，这表明这种 3-羟基-3-甲基戊二酰基辅酶 A 还原酶抑制剂有另一种潜在的治疗应用。
