Department of Pharmacology, The University of Tokushima Graduate School, Tokushima, Japan.
Pharmacology. 2012;90(5-6):324-31. doi: 10.1159/000343244. Epub 2012 Oct 9.
BACKGROUND/AIMS: Tumor necrosis factor-α (TNF-α) is known to involve the progression of renal dysfunction through its cytotoxicity and proinflammatory effects such as the induction of intercellular adhesion molecule (ICAM)-1 expression in vascular endothelial cells (ECs). Olmesartan, one of the angiotensin II type 1 receptor blockers (ARBs), has been reported to show protective effects on injured ECs by some causal factors of renal disorder other than angiotensin II. However, the effects of olmesartan on TNF-α-induced glomerular EC damage have not been investigated. In the present study, we investigated the effects of RNH-6270, an active metabolite of olmesartan, on TNF-α-induced human glomerular EC (HGEC) damage to clarify the renoprotective mechanisms of ARBs.
Cultured HGECs were stimulated by TNF-α, and then cell viability and cytotoxicity were measured by MTT assay and lactate dehydrogenase release assay, respectively. TNF-α-induced oxidative stress was estimated by dihydroethidium assay and lucigenin chemiluminescence assay. ICAM-1 expression and the phosphorylations of mitogen-activated protein kinases were measured using Western blotting assay.
RNH-6270 suppressed cell death and the increase in ICAM-1 expression induced by TNF-α via the inhibition of reactive oxygen species in HGECs.
Our findings suggested that olmesartan might have protective effects against TNF-α-induced glomerular EC dysfunction.
背景/目的：肿瘤坏死因子-α（TNF-α）通过其细胞毒性和促炎作用（如诱导血管内皮细胞[ECs]中细胞间黏附分子[ICAM]-1 的表达）而参与肾功能障碍的进展。血管紧张素 II 型 1 型受体阻滞剂（ARB）之一的奥美沙坦已被报道通过除血管紧张素 II 之外的一些肾脏疾病的因果因素对受损的 ECs 显示出保护作用。然而，奥美沙坦对 TNF-α诱导的肾小球 EC 损伤的影响尚未得到研究。在本研究中，我们研究了 RNH-6270（奥美沙坦的一种活性代谢物）对 TNF-α诱导的人肾小球 EC（HGEC）损伤的影响，以阐明 ARB 的肾脏保护机制。
用 TNF-α刺激培养的 HGECs，然后通过 MTT 测定法和乳酸脱氢酶释放测定法分别测量细胞活力和细胞毒性。通过二氢乙啶测定法和荧光素化学发光法评估 TNF-α诱导的氧化应激。使用 Western blot 测定法测量 ICAM-1 表达和丝裂原活化蛋白激酶的磷酸化。
RNH-6270 通过抑制 HGECs 中的活性氧来抑制 TNF-α诱导的细胞死亡和 ICAM-1 表达的增加。
我们的研究结果表明，奥美沙坦可能对 TNF-α诱导的肾小球 EC 功能障碍具有保护作用。
