Anti-renal fibrosis effect of asperulosidic acid via TGF-β1/smad2/smad3 and NF-κB signaling pathways in a rat model of unilateral ureteral obstruction
Anti-renal fibrosis effect of asperulosidic acid via TGF-β1/smad2/smad3 and NF-κB signaling pathways in a rat model of unilateral ureteral obstruction
复制标题
阿perulosidic酸通过TGF-β1/smad2/smad3和NF-κB信号通路在单侧输尿管梗阻大鼠模型中的抗肾纤维化作用
DOI：
10.1016/j.phymed.2018.09.009
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发表时间：
2019-02-01
期刊：
影响因子：
7.9
通讯作者：
Liu, Menghua
中科院分区：
文献类型：
--
作者：
Lu, Xianyuan;Zou, Wei;Liu, Menghua
背景：肾纤维化是导致终末期肾病的最常见途径。其特征在于过量的细胞外基质（ECM）积聚和肾组织损伤，随后导致肾衰竭。阿魏酸（ASPA）是一种具有生物活性的环烯醚萜苷类化合物，具有抗肿瘤、抗氧化、抗炎等作用，但其对单侧输尿管梗阻（UUO）所致肾纤维化的影响尚未见报道。目的：研究阿魏酸对UUO所致肾纤维化的保护作用，并探讨其药理学机制。36只SD大鼠随机分为假手术组、UUO模型组、ASPA治疗组（10、20、40 mg/kg）和卡托普利组（20 mg/kg）。大鼠每天一次连续14天腹腔内给予溶剂、ASPA或卡托普利。分别于造模后第7、10、14天检测血清尿素氮（BUN）、尿酸（UA）及炎症因子水平。第14天取12 h尿测定尿蛋白（upro）含量。造模后第14天取梗阻肾组织行HE染色和Masson三色染色，并进行免疫组化染色。结果：UUO模型大鼠血清尿素氮（BUN）、尿酸（UA）、尿蛋白原（upro）水平升高，ASPA治疗后BUN、UA、尿蛋白原（upro）水平降低，肾功能改善。ASPA给药（10、20和40 mg/kg）后，肿瘤坏死因子-α（TNF-α）、白细胞介素-1 β（IL-1 β）和IL-6的蛋白水平以及TNF-α、IL-1 β、IL-6、单核细胞趋化蛋白-1（MCP-1）和干扰素-γ（IFN-γ）的mRNA水平以剂量依赖性方式降低。ASPA可通过抑制核因子-κ B（NF-κ B）通路减轻炎症反应。此外，ASPA以20和40 mg/kg剂量给药后，观察到α-平滑肌肌动蛋白（α-SMA）、胶原蛋白III和纤连蛋白表达减少。结论：ASPA对UUO大鼠肾间质纤维化具有保护作用。这些作用可能是通过抑制NF-κ B和TGF-β 1/smad 2/smad 3信号通路的活化。
Background: Renal fibrosis is the most common pathway leading to end-stage renal disease. It is characterized by excess extracellular matrix (ECM) accumulation and renal tissue damage, subsequently leading to kidney failure. Asperulosidic acid (ASPA), a bioactive iridoid glycoside, exerts anti-tumor, anti-oxidant, and anti-inflammatory activities, but its effects on renal fibrosis induced by unilateral ureteral obstruction (UUO) have not yet been investigated.Purpose: This study aimed to investigate the protective effect of ASPA on renal fibrosis induced by UUO, and to explore its pharmacological mechanism.Methods: Thirty-six Sprague-Dawley (SD) rats were randomly divided into six groups: sham group, UUO model group, three ASPA treatment groups (10, 20, and 40 mg/kg), and captopril group (20 mg/kg). Rats were administered vehicle, ASPA or captopril intraperitoneally once a day for 14 consecutive days. Urea nitrogen (BUN), uric acid (UA) and inflammatory factors in serum samples were evaluated on the 7th, 10th, and 14th day after renal fibrosis induction. In addition, the 12 h urine was collected to test the content of urinary protein (upro) on the 14th day. The obstructive renal tissues were collected for pathological analysis (hematoxylin and eosion (H&E) staining and Masson's Trichrome staining) and immunohistochemical analysis on the 14th day after renal fibrosis induction. The mRNA expression of related factors and the protein levels of smad2, smad3, and smad4 were measured in UUO-induced rats by real time PCR and Western blot, respectively.Results: The levels of BUN, UA, and upro were elevated in UUO-induced rats, but ASPA treatment improved renal function by reducing the levels of BUN, UA, and upro. The protein levels of tumor necrosis factor-alpha(TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-6, as well as the mRNA levels of TNF-alpha, IL-1 beta, IL-6, monocyte chemoattractant protein-1 (MCP-1) and interferon-gamma (IFN-gamma), were decreased after ASPA administration (10, 20 and 40 mg/kg) in a dose-dependent manner. The ASPA exerted an alleviation effect on the inflammatory response through inhibition of nuclear factor-kappa B (NF-kappa B) pathway. In addition, reductions in alpha-smooth muscle actin (alpha-SMA), collagen III, and fibronectin expression were observed after ASPA administration at doses of 20 and 40 mg/kg. Furthermore, the renal expression of transforming growth factor-beta 1 (TGF-beta 1), smad2, smad3, and smad4 was down-regulated by ASPA treatment at doses of 20 and 40 mg/kg.Conclusion: ASPA possessed protective effects on renal interstitial fibrosis in UUO-induced rats. These effects may be through inhibition of the activation of NF-kappa B and TGF-beta 1/smad2/smad3 signaling pathways.