从沉默信号调节因子对自噬的积极调控探讨糖尿病肾病防治新靶点
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摘要
糖尿病肾病是终末期肾病的主要原因。自噬对于肾脏中固有细胞的稳定和功能维持是一种不可缺少的生存机制。随年龄增长,肾脏作为一个极易受损伤的特殊靶器官,糖尿病导致的肾脏长期自噬失调而加速肾脏细胞损伤和衰老。而沉默信号调节因子(SIRT1)在肾脏组织中广泛表达,近年来已发现SIRT1在肾脏疾病发生发展中发挥了重要保护作用。作者综述了营养物质敏感信号通路中的SIRT1对自噬的积极调控,探讨了SIRT1成为糖尿病肾病的治疗靶点的可能性,并提出未来的研究方向。
Diabetic nephropathy(DN) is the main cause of end-stage nephropathy. Autophagy is an indispensablesurvival mechanism for the stability and functional maintenance of the inherent cells in the kidney. The vulnerabilityof the kidney as a special target organ to injury increases with age, which accelerates renal cell damage andsenescence due to long-term autophagy disorder caused by diabetes. In recent years,it has been found that SIRT1 plays an important role in the pathogenesis and development of renal disease. We discuss the possibility of activeregulation of autophagy by SIRT1 in nutrient sensitive signaling pathway as a therapeutic target for diabeticnephropathy and propose the future research direction.
Diabetic nephropathy(DN) is the main cause of end-stage nephropathy. Autophagy is an indispensablesurvival mechanism for the stability and functional maintenance of the inherent cells in the kidney. The vulnerabilityof the kidney as a special target organ to injury increases with age, which accelerates renal cell damage andsenescence due to long-term autophagy disorder caused by diabetes. In recent years,it has been found that SIRT1 plays an important role in the pathogenesis and development of renal disease. We discuss the possibility of activeregulation of autophagy by SIRT1 in nutrient sensitive signaling pathway as a therapeutic target for diabeticnephropathy and propose the future research direction.
引文
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[35]PENG J,LI X,ZHANG D,et al.Hyperglycemia,p53 and mitochondrial pathway of apoptosis are involved in the susceptibility of diabetic models to ischemic acute kidney injury[J].Kidney International,2015,87(1):137-150.
[36]WANG X L,WU L Y,ZHAO L,et al.SIRT1 activator ameliorates the renal tubular injury induced by hyperglycemia in vivo and in vitro via inhibiting apoptosis[J].Biomedicine&pharmacotherapy,2016,83:41.
[37]KITADA M,TAKEDA A,NAGAI T,et al.Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of SIRT1 in diabetic Wistar fatty(fa/fa)rats:a model of type 2 diabetes[J].Experimental Diabetes Research,2011,2011:908185.
[38]李隽雨.自噬的分子机制及其与中医的联系[J].浙江中西医结合杂志,2017,27(5):447-449.
[39]黄贵华,纪云西,吴大力,等.细胞自噬与中医气虚痰瘀关系探讨[J].中医杂志,2011,52(20):1717-1719.
[2]WHEELOCK K M,JAISWAL M,MARTIN C L,et al.Cardiovascular autonomic neuropathy associates with nephropathy lesions in American Indians with type 2 diabetes[J].J Diabetes Complications,2016,30(5):873-879.
[3]CHOI A M,RYTER S W,LEVINE B,et al.Autophagy in human health and disease[J].The New England Journal of Medicine,2013,368(7):651-662.
[4]方钱华,李春君.足细胞自噬与糖尿病肾病[J].国际内分泌代谢杂志,2017,37(4):242-245.
[5]曹荣,张晓燕,康继宏,等.Sirt1在肾脏疾病中的作用[J].生理科学进展,2013,44(4):305-309.
[6]GUCLU A,ERDUR F M,TURKMEN K.The Emerging role of sirtuin 1 in cellular metabolism,diabetes mellitus,diabetic kidney disease and hypertension[J].Experimental and Clinical Endocrinology&Diabetes,2015,124(3):131-139.
[7]DING Y,CHOI M E.Autophagy in diabetic nephropathy[J].Journal of Endocrinology,2015,224(1):R15.
[8]朱淑媛,鲍晓荣.糖尿病肾病足细胞自噬异常的机制研究进展[J].中国中西医结合肾病杂志,2017,18(6):561-562.
[9]MIZUSHIMA N,LEVINE B,CUERVO AM,et al.Autophagy fights disease through cellular self-digestion[J].Nature,2008,451:1069-1075.
[10]KROEMER G,MARINO G,LEVINE B.Autophagy and the integrated stress response[J].Molecular Cell,2010,40(2):280-293.
[11]KITADA M,OGURA Y,MONNO I,et al.Regulating autophagy as a therapeutic target for diabetic nephropathy[J].Current Diabetes Reports,2017,17(7):53.
[12]KUME S,KOYA D,UZU T,et al.Role of nutrient-sensing signals in the pathogenesis of diabetic nephropathy[J].Biomed Research International,2014,2014(8):315494.
[13]GIBLIN W,SKINNER M E,LOMBARD D B,et al.Sirtuins:guardians of mammalian healthspan[J].Trends in Genetics,2014,30(7):271-286.
[14]POLAKJONKISZ D,LASZKISZCZACHOR K,REHAN L,et al.Nephroprotective action of sirtuin 1(SIRT1)[J].Journal of Physiology&Biochemistry,2013,69(4):957-961.
[15]GLICK D,BARTH S,MACLEOD K F.Autophagy:cellular and molecular mechanisms[J].The Journal of Pathology,2010,221(1):3-12..
[16]KAUFMANN A,BEIER V,FRANQUELIM H G,et al.Molecular mechanism of autophagic membrane-scaffold assembly and disassembly[J].Cell,2014,156(3):469-81.
[17]SHINJI K,DAISUKE K.Autophagy:A novel therapeutic target for diabetic nephropathy[J].Diabetes&Metabolism Journal,2015,39(6):451.
[18]LIU B,ZHANG B,GUO R,et al.Enhancement in efferocytosis of oxidized low-density lipoprotein-induced apoptotic RAW264.7 cells through SIRT1-mediated autophagy[J].International Journal of Molecular Medicine,2014,33(3):523-533.
[19]LIU S,HARTLEBEN B,KRETZ O,et al.Autophagy plays a critical role in kidney tubule maintenance,aging and ischemiareperfusion injury[J].Autophagy,2012,8(5):826-837.
[20]KITADA M,KUME S,AI T W,et al.Sirtuins and renal diseases:relationship with aging and diabetic nephropathy[J].Clinical Science,2013,124(3):153-64.
[21]WANG X,GAO L,LIN H,et al.Mangiferin prevents diabetic nephropathy progression and protects podocyte function via autophagy in diabetic rat glomeruli[J].European Journal of Pharmacology,2018,824:170-178.
[22]TAGAWA A,YASUDA M,KUME S,et al.Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy[J].Diabetes,2015,65(3):755-767.
[23]NAKATANI Y,INAGI R.Epigenetic regulation through SIRT1 in podocytes[J].Current Hypertension Reviews,2016,12(2):89-94.
[24]邓宇菲,鲍晓荣.糖尿病肾病大鼠足细胞自噬的变化[J].中国中西医结合肾病杂志,2016,17(12):1082-1084.
[25]LIU R,ZHONG Y,LI X,et al.Role of transcription factor acetylation in diabetic kidney disease[J].Diabetes,2014,63(7):2440.
[26]HUANG S S,DING D F,CHEN S,et al.Resveratrol protects podocytes against apoptosis via stimulation of autophagy in a mouse model of diabetic nephropathy[J].Sci Rep,2017,7:45692.
[27]ROGACKA D,AUDZEYENKA I,RYCHLOWSKI M,et al.Metformin overcomes high glucose-induced insulin resistance of podocytes by pleiotropic effects on SIRT1 and AMPK[J].Biochim Biophys Acta,2017,1864(1):115-125.
[28]GU J,YANG M,QI N,et al.Olmesartan prevents microalbuminuria in db/db diabetic mice through inhibition of angiotensin II/p38/SIRT1-Induced podocyte apoptosis[J].Kidney&Blood Pressure Research,2016,41(6):848.
[29]LU M M,YIN N C,LIU W et al.Curcumin ameliorates diabetic nephropathy by suppressing NLRP3 inflammasome signaling[J].BioMed Research International,2017,2017:1516985.
[30]白咪.SIRT1通过线粒体自噬阻断NLRP3炎症小体活化和足细胞损伤[D].南京:南京医科大学,2016.
[31]TANG S C,LAI K N.The pathogenic role of the renal proximal tubular cell in diabetic nephropathy[J].Nephrology Dialysis Transplantation,2012,27(8):3049-3056.
[32]YAMAMOTO T,TAKABATAKE Y,KIMURA T,et al.Timedependent dysregulation of autophagy:Implications in aging and mitochondrial homeostasis in the kidney proximal tubule[J].Autophagy,2016,12(5):801-813.
[33]MA L,FU R,DUAN Z,et al.SIRT1 is essential for resveratrol enhancement of hypoxia-induced autophagy in the type 2 diabetic nephropathy rat[J].Pathology Research&Practice,2016,212(4):310.
[34]KUME S,UZU T,HORIIKE K,et al.Calorie restriction enhances cell adaptation to hypoxia through SIRT1-dependent mitochondrial autophagy in mouse aged kidney[J].Journal of Clinical Investigation,2010,120(4):1043-1055.
[35]PENG J,LI X,ZHANG D,et al.Hyperglycemia,p53 and mitochondrial pathway of apoptosis are involved in the susceptibility of diabetic models to ischemic acute kidney injury[J].Kidney International,2015,87(1):137-150.
[36]WANG X L,WU L Y,ZHAO L,et al.SIRT1 activator ameliorates the renal tubular injury induced by hyperglycemia in vivo and in vitro via inhibiting apoptosis[J].Biomedicine&pharmacotherapy,2016,83:41.
[37]KITADA M,TAKEDA A,NAGAI T,et al.Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of SIRT1 in diabetic Wistar fatty(fa/fa)rats:a model of type 2 diabetes[J].Experimental Diabetes Research,2011,2011:908185.
[38]李隽雨.自噬的分子机制及其与中医的联系[J].浙江中西医结合杂志,2017,27(5):447-449.
[39]黄贵华,纪云西,吴大力,等.细胞自噬与中医气虚痰瘀关系探讨[J].中医杂志,2011,52(20):1717-1719.