褪黑素对大鼠纤维化TGF-β_1/Smads信号通路干预研究
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摘要
褪黑素是一种主要由松果体分泌的多效性神经激素,具有多种生物学功能,包括抗氧化应激、抗炎、抗凋亡和抗肿瘤特性,以及调节昼夜节律。为探寻临床治疗肾间质纤维化的新途径,本试验观察褪黑素对单侧输尿管梗阻(UUO)构建大鼠肾纤维化模型TGF-β_1/Smads信号通路影响,探讨其干预对肾纤维化机制,SD大鼠随机分为假手术(Sham)组、UUO模型(UUO)组、UUO+5mg·kg~(-1)褪黑素组、UUO+10mg·kg~(-1)褪黑素组、UUO+15mg·kg~(-1)褪黑素组,每组6只。均于手术当天晚上灌胃给药,每24h1次。14d处死大鼠,取血清检测血肌酐、尿素氮,肾组织进行Masson染色,观察病理结果,实时定量PCR检测肾组织TGF-β_1、Smad3、Smad7和Collagen Type I mRNA表达。结果表明:褪黑素减轻肾组织纤维化病理损伤,使肾组织TGF-β_1、Smad3、Collagen Type I mRNA表达降低,Smad7mRNA表达升高(P<0.05,部分P<0.01),以15mg·kg~(-1)改善效果最佳。褪黑素可呈剂量相关性下调TGF-β_1、Smad3、Collagen Type I及上调Smad7来抑制TGF-β_1/Smads信号通路,从而发挥肾间质纤维化作用。
Melatonin is a pleiotropic neurohormone secreted mainly by the pineal gland.It has a variety of biological functions including anti-oxidative stress,anti-inflammatory,anti-apoptotic and anti-tumor properties,as well as regulation of circadian rhythm.In order to explore a new way to prevent renal interstitial fibrosis.In this study we observed the effect of melatonin on the unilateral ureteral obstruction(UUO)constructing the renal fibrosis model,SD rats were randomly divided into sham operation group,UUO model(UUO)group,UUO + 5mg·kg~(-1) melatonin group,UUO +10mg·kg~(-1) melatonin group,UUO + 15mg·kg~(-1) melatonin group,each group 6.They were administered by intragastric administration on the evening of the operation,once every 24 hours.The rats were sacrificed for 14 days.Serum creatinine and urea nitrogen were detected by serum.Masson staining was used to observe the pathological results of kidney tissue.The expressions of TGF-β_1,Smad3,Smad7 and Collagen Type I mRNA were detected by real-time quantitative PCR.The results showed that melatonin reduced the pathological damage of renal fibrosis,decreased the expression of TGF-β_1,Smad3 and Collagen Type I mRNA,and increased the expression of Smad7 mRNA(P<0.05,part P<0.01)to 15mg·kg~(-1) improves best.Melatonin can down-regulate TGF-β_1,Smad3,Collagen Type I and up-regulate Smad7 to inhibit TGF-β_1/Smads signaling pathway,thereby exerting renal interstitial fibrosis.
Melatonin is a pleiotropic neurohormone secreted mainly by the pineal gland.It has a variety of biological functions including anti-oxidative stress,anti-inflammatory,anti-apoptotic and anti-tumor properties,as well as regulation of circadian rhythm.In order to explore a new way to prevent renal interstitial fibrosis.In this study we observed the effect of melatonin on the unilateral ureteral obstruction(UUO)constructing the renal fibrosis model,SD rats were randomly divided into sham operation group,UUO model(UUO)group,UUO + 5mg·kg~(-1) melatonin group,UUO +10mg·kg~(-1) melatonin group,UUO + 15mg·kg~(-1) melatonin group,each group 6.They were administered by intragastric administration on the evening of the operation,once every 24 hours.The rats were sacrificed for 14 days.Serum creatinine and urea nitrogen were detected by serum.Masson staining was used to observe the pathological results of kidney tissue.The expressions of TGF-β_1,Smad3,Smad7 and Collagen Type I mRNA were detected by real-time quantitative PCR.The results showed that melatonin reduced the pathological damage of renal fibrosis,decreased the expression of TGF-β_1,Smad3 and Collagen Type I mRNA,and increased the expression of Smad7 mRNA(P<0.05,part P<0.01)to 15mg·kg~(-1) improves best.Melatonin can down-regulate TGF-β_1,Smad3,Collagen Type I and up-regulate Smad7 to inhibit TGF-β_1/Smads signaling pathway,thereby exerting renal interstitial fibrosis.
引文
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[5] Kennaway D J.Are the proposed benefits of melatonin-rich foods too hard to swallow?[J].Critical Reviews in Food Science and Nutrition,2017,57(5):958-962.
[6] Choi H S,KangJ W.Melatonin attenuates carbon tetrachloride-induced liver fibrosis via inhibition of necroptosis[J].Translational Research,2015,166(3):292-303.
[7] Bae J S,Kim S M,Lee H.The Hippo signaling pathway provides novel anti-cancer drug targets[J].Oncotarget,2017,8(9):16084-16098.
[8] Dwivedi S K,McMeekin S D,Slaughter K.Role of TGF-βsignaling in uterine carcinosarcoma[J].Bhattacharya Roncotarget,2015,6(16):14646-14655.
[9] Agnieszka L,Mateusz S,Alicja J,et al.TGF-β1/Smads and miR-21in renal fibrosis and inflammation[J].Mediators of Inflammation,2016:8319283.
[10]程小红,于小勇,毛加荣.IgA肾病的病理改变与中医微观辨证[J].中国中西医结合肾病杂志,2014,15(2):185-186.
[2]周丹,沈延春,王芳,等.褪黑素对慢性肾衰竭大鼠肾脏的保护作用[J].医药导报,2009(12):1535-1539.
[3]邹经纬,凌月福.褪黑素的研究进展及对肾脏的保护作用[J].中国医药科学,2013(5):51-53,73.
[4]武贵群,高翔,梅长林.TGF-β/Smads通路与肾脏纤维化研究进展[J].中国中西医结合肾病杂志,2012(5):459-461.
[5] Kennaway D J.Are the proposed benefits of melatonin-rich foods too hard to swallow?[J].Critical Reviews in Food Science and Nutrition,2017,57(5):958-962.
[6] Choi H S,KangJ W.Melatonin attenuates carbon tetrachloride-induced liver fibrosis via inhibition of necroptosis[J].Translational Research,2015,166(3):292-303.
[7] Bae J S,Kim S M,Lee H.The Hippo signaling pathway provides novel anti-cancer drug targets[J].Oncotarget,2017,8(9):16084-16098.
[8] Dwivedi S K,McMeekin S D,Slaughter K.Role of TGF-βsignaling in uterine carcinosarcoma[J].Bhattacharya Roncotarget,2015,6(16):14646-14655.
[9] Agnieszka L,Mateusz S,Alicja J,et al.TGF-β1/Smads and miR-21in renal fibrosis and inflammation[J].Mediators of Inflammation,2016:8319283.
[10]程小红,于小勇,毛加荣.IgA肾病的病理改变与中医微观辨证[J].中国中西医结合肾病杂志,2014,15(2):185-186.