Yao Q, Ayala E Rodríguez, Qian J Q, Stenvinkel P, Axelsson J, Lindholm B
Department of Clinical Science, Intervention and Technology, Division of Baxter Novum, Karolinska Institute, Stockholm, Sweden.
Clin Nephrol. 2007 Nov;68(5):295-301.
Human peritoneal mesothelial cells (HPMCs) have been shown to regulate the inflammatory response and the subsequent peritoneal extracellular matrix accumulation (ECM) induced by bio-incompatible peritoneal dialysis solutions. Recently, attention has been given to the possible antiinflammatory effect exhibited by angiotensin receptor blockers (ARB) or PPAR-gamma agonists in several tissues including glomerular. As no data on the potential role of these commonly used drugs in reducing peritoneal fibrosis exist, we examined the in vitro effects of an ARB (losartan) and a PPAR-gamma agonist (rosiglitazone) on inflammatory and profibrotic pathways in cultured HPMCs subjected to high glucose.
HPMCs were incubated for 48 hours with 3 different concentrations of glucose: 5 mM (G5), 50 mM (G50) and 100 mM (G100), as well as G50 with either losartan (5 or 10 microM) and/or rosiglitazone (1 or 10 microM). IL-6, IL-8, VEGF and TGF-beta1 in the supernatants were measured by cytokine multiplex assays or ELISA. Smad7, the inhibitor of the TGF/Smad signaling pathway, was measured using immunocytochemistry.
All the measured cytokines increased in proportion to increased concentration of glucose. Unexpectedly, this effect was not inhibited, but rather further enhanced, by rosiglitazone and losartan separately. However, only the combination of the two drugs had an inhibitory effect on TGF- beta1 and IL-6, while the expression of inhibitory Smad7 was increased.
We conclude that high glucose exposure stimulates an inflammatory response in HPMCs in a dose-dependent manner. Rosiglitazone and losartan appear to have synergetic effects which could decrease fibrosis by inhibiting inflammation and regulating the TGF/Smad signaling pathway, but further studies are needed to elucidate the complex pathways modulated by these drugs.
已证实人腹膜间皮细胞（HPMCs）可调节由生物不相容性腹膜透析液诱导的炎症反应及随后的腹膜细胞外基质积聚（ECM）。最近，血管紧张素受体阻滞剂（ARB）或过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂在包括肾小球在内的多种组织中表现出的可能抗炎作用受到关注。由于尚无关于这些常用药物在减轻腹膜纤维化方面潜在作用的数据，我们研究了ARB（氯沙坦）和PPAR-γ激动剂（罗格列酮）对高糖培养的HPMCs中炎症和促纤维化途径的体外影响。
将HPMCs与3种不同浓度的葡萄糖（5 mM（G5）、50 mM（G50）和100 mM（G100））以及G50与氯沙坦（5或10 μM）和/或罗格列酮（1或10 μM）一起孵育48小时。通过细胞因子多重检测或酶联免疫吸附测定（ELISA）测量上清液中的白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、血管内皮生长因子（VEGF）和转化生长因子-β1（TGF-β1）。使用免疫细胞化学法测量TGF/Smad信号通路的抑制剂Smad7。
所有测量的细胞因子均随葡萄糖浓度升高而呈比例增加。出乎意料的是，罗格列酮和氯沙坦单独使用时并未抑制这种作用，反而进一步增强了这种作用。然而，只有两种药物联合使用对TGF-β1和IL-6有抑制作用，同时抑制性Smad7的表达增加。
我们得出结论，高糖暴露以剂量依赖方式刺激HPMCs中的炎症反应。罗格列酮和氯沙坦似乎具有协同作用，可通过抑制炎症和调节TGF/Smad信号通路来减少纤维化，但需要进一步研究以阐明这些药物调节的复杂途径。
