Department of Internal Medicine, Busan Medical Center, Busan, Republic of Korea.
Am J Nephrol. 2013;37(1):7-15. doi: 10.1159/000345990. Epub 2012 Dec 21.
BACKGROUND/AIM: Cyclosporine (CsA)-induced kidney injury is characterized by renal dysfunction with inflammatory cell infiltrations, apoptosis and fibrosis. Pleiotropic effects of statins may exert anti-inflammatory, antiapoptotic and antifibrotic actions beyond lipid control. The aim of this study is to investigate whether rosuvastatin (RUS) has anti-inflammatory, antiapoptotic and antifibrotic effects on chronic CsA-induced nephropathy in a rat model.
Male Sprague-Dawley rats fed a low-sodium diet were divided into three treatment groups: control (0.9% saline injection), CsA (15 mg/kg/day by subcutaneous injection), CsA + RUS (10 mg/kg/day by gastric gavage). Renal function, CsA level and lipid levels were measured at the end of 4 weeks. The expression of ED-1, transforming growth factor-β(1) (TGF-β(1)) and α-smooth muscle actin (α-SMA) for inflammation and fibrosis were examined by Western blot analysis. The expression levels of apoptosis-associated factors were examined by Western blot analysis. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling (TUNEL) method.
Kidney function was decreased in CsA-treated rats compared with controls, which was attenuated by RUS. RUS did not affect the lipid level or the blood CsA level. TUNEL staining showed that RUS inhibited CsA-induced tubular apoptosis. RUS decreased CsA-induced increased expression of Bax/Bcl-2 ratio. The expressions of ED-1, α-SMA, TGF-β(1), Smad2/3, Smad4 and p-JNK were increased in CsA-treated rats, which were attenuated by RUS. Tubular atrophy and interstitial fibrosis in CsA-treated rats were attenuated by RUS supplementation.
RUS supplementation attenuates proinflammatory and apoptosis-related factors and inhibits the fibrotic pathways including the smad-dependent and smad-independent pathways in a rat model of CsA-induced nephropathy.
背景/目的：环孢素（CsA）诱导的肾损伤的特征是肾功能障碍伴有炎症细胞浸润、细胞凋亡和纤维化。他汀类药物的多效作用可能具有抗炎、抗凋亡和抗纤维化作用，超出了脂质控制的范围。本研究旨在探讨罗苏伐他汀（RUS）在大鼠慢性 CsA 肾病模型中是否具有抗炎、抗凋亡和抗纤维化作用。
雄性 Sprague-Dawley 大鼠给予低钠饮食，分为三组：对照组（0.9%生理盐水注射）、CsA 组（15mg/kg/天皮下注射）、CsA+RUS 组（10mg/kg/天灌胃）。4 周后测量肾功能、CsA 水平和血脂水平。Western blot 分析检测 ED-1、转化生长因子-β1（TGF-β1）和α-平滑肌肌动蛋白（α-SMA）的表达，以评估炎症和纤维化。Western blot 分析检测凋亡相关因子的表达水平。末端脱氧核苷酸转移酶介导的生物素 Nick 末端标记（TUNEL）法评估细胞凋亡。
与对照组相比，CsA 治疗组大鼠肾功能下降，RUS 可减轻这种下降。RUS 不影响血脂水平或血 CsA 水平。TUNEL 染色显示 RUS 抑制 CsA 诱导的肾小管细胞凋亡。RUS 降低了 CsA 诱导的 Bax/Bcl-2 比值增加。CsA 治疗组大鼠 ED-1、α-SMA、TGF-β1、Smad2/3、Smad4 和 p-JNK 的表达增加，RUS 可减轻这些增加。RUS 补充可减轻 CsA 治疗大鼠的肾小管萎缩和间质纤维化。
RUS 补充可减轻大鼠 CsA 肾病模型中促炎和凋亡相关因子，并抑制包括 Smad 依赖和非依赖途径在内的纤维化途径。
