mTOR信号通路在糖尿病肾病发病机制中作用的研究进展
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摘要
糖尿病肾病是目前终末期肾脏疾病的主要原因,给患者家庭及社会带来沉重负担,如何预防及治疗糖尿病肾病成为亟需解决的问题。然而,糖尿病肾病的发病机制极其复杂,其中mTOR信号通路在其中扮演着重要角色。该综述主要总结了mTOR信号通路对糖尿病肾病的影响并阐述其可能存在的机制,希望能够给予同行些许借鉴。
Diabetic nephropathy, one of the main causes of end-stage renal disease, not only brings a heavy burden to a family, but also becomes a big prolem to society nowadays. Preventing and curing the disease have become an urgent problem to be solved. However, the pathogenesis of diabetes kidney disease is so complex that it is extremely hard to deal with, in which mTOR signaling pathway plays an important role. This review mainly summarizes the effect of mTOR signal pathway on diabetes kidney disease and elaborates the possible mechanism, hoping to give some reference to the peers.
Diabetic nephropathy, one of the main causes of end-stage renal disease, not only brings a heavy burden to a family, but also becomes a big prolem to society nowadays. Preventing and curing the disease have become an urgent problem to be solved. However, the pathogenesis of diabetes kidney disease is so complex that it is extremely hard to deal with, in which mTOR signaling pathway plays an important role. This review mainly summarizes the effect of mTOR signal pathway on diabetes kidney disease and elaborates the possible mechanism, hoping to give some reference to the peers.
引文
[1]Wu F, Li S, Zhang N, et al. Hispidulin alleviates highglucose-induced podocyte injury by regulating protective autophagy. Biomed Pharmacother, 2018, 104:307-14
[2]YuanCM,NeeR,CeckowskiKA,etal.Diabetic nephropathy as the cause of end-stage kidney disease reported on the medical evidence form CMS2728 at a single center. Clin Kidney J, 2017, 10:257-62
[3]Lee EJ, Kang MK, Kim DY. Chrysin inhibits advanced glycation end products-induced kidney fibrosis in renal mesangial cells and diabetic kidneys. Nutrients, 2018, 10:882
[4]Han P, Zhan H, Shao M, et al. Niclosamide ethanolamine improves kidney injury in db/db mice. Diabetes Res Clin Pract, 2018, 144:25-33
[5]Yang H, Jiang X, Li B, et al. Structural mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.Nature, 2017, 552:368-73
[6]Benavides-Serrato A, Lee J, Holmes B, et al. Specific blockade of Rictor-mTOR association inhibits mTORC2activity and is cytotoxic in glioblastoma, 2017, 12:E1176
[7]Dibble CC, Elis W, Menon S, et al. TBC1D7 is a third subunitofthe TSC1-TSC2complexupstreamof mTORC1. Mol Cell, 2012, 47:535-46
[8]Peng H, Kasada A, Ueno M, et al. Distinct roles of Rheb and raptor in activating mTOR complex 1 for the selfrenewal of hematopoietic stem cells. Biochem Biophys Res Commun, 2018, 495:1129-35
[9]Yang G, Murashige DS, Humphrey SJ, et al. A positive feedback loop between Akt and mTORC2 via SIN1phosphorylation. Cell Rep, 2015, 12:937-43
[10]Bera A, Das F, Ghosh-Choudhury N, et al. Reciprocal regulation of miR-214 and PTEN by high glucose regulates renal glomerular mesangial and proximal tubular epithelial cell hypertrophy and matrix expansion. Am J Physiol Cell Physiol, 2017, 313:C430-47
[11]Han F, Xue M, Chang Y, et al. Triptolide suppresses glomerular mesangial cell proliferation in diabetic nephropathy is associated with inhibition of PDK1/Akt/mTOR pathway. Int J Biol Sci, 2017, 13:1266-75
[12]Chen J, Zhao D, Zhu M, et al. Paeoniflorin ameliorates AGEs-induced mesangial cell injury through inhibiting RAGE/mTOR/autophagy pathway. Biomed Pharmacother,2017, 89:1362-9
[13]Das F, Ghosh-Choudhury N, Mariappan MM, et al.Hydrophobic motif site-phosphorylated protein kinase CII between mTORC2 and Akt regulates high glucose-induced mesangial cell hypertrophy. Am J Physiol Cell Physiol,2016, 310:C583-96
[14]Sha W, Shen L, Zhou L, et al. Silencing of CXCL12performs a protective effect on C5b-9-induced injury in podocytes. Int Urol Nephrol, 2018, 50:1535-44
[15]G?del M, Hartleben B, Herbach N, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest, 2011, 121:2197-209
[16]Han P,Shao M,Guo L, et al. Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice.Am J Transl Res, 2018, 10:1071-84
[17]Park JM, Jung CH, Seo M, et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14.Autophagy, 2016, 12:547-64
[18]Yang D, Livingston MJ, Liu Z, et al. Autophagy in diabetic kidney disease:regulation, pathological role and therapeutic. Cell Mol Life Sci, 2018, 75:669-88
[19]Tu Y, Gu L, Chen D, et al. Rhein inhibits autophagy in rat renaltubularcellsbyregulationof AMPK/mTOR signaling. Sci Rep, 2017, 7:43790
[20]Yamahara K, Kume S, Koya D, et al. Obesity-mediated autophagy insufciency exacerbates proteinuria-induced tubulointerstitial lesions. J Am Soc Nephrol, 2013, 24:1769-81
[21]Cin DP, Onay T, Paltoo A, et al. Inhibition of mTOR disrupts autophagic flux in podocytes. J Am Soc Nephrol,2012, 23:412-20
[22]Liu Y, Zhang J, Wang Y, et al. Apelin involved in progressionofdiabeticnephropathybyinhibiting autophagy in podocyte. Cell Death Dis, 2017, 8:e3006
[23]Xiao T, Guan X, Nie L, et al. Rapamycin promotes podocyte autophagy and ameliorates renal injury in diabetic mice. Mol Cell Biochem, 2014, 394:145-54
[24]Wang X, Gao L, Lin H, et al. Mangiferin prevents diabetic nephropathy progression and protects podocyte function via autophagy in diabetic rat glomeruli. Eur J Pharmacol,2018, 824:170-8
[25]Eid S, Boutary S, Braych K, et al. mTORC2 signaling regulates nox4-induced podocyte depletion in diabetes.Antioxid Redox Signal, 2016, 25:703-19
[26]Mariappan MM, Feliers D, Mummidi S, et al. High glucose, high insulin, and their combination rapidly induce laminin-beta1 synthesis by regulation of mRNA translation in renal epithelial cells. Diabetes. 2007, 56:476-85
[27]Lieberthal W, Levine JS. The role of the mammalian target of rapamycin(mTOR)in renal disease. J Am Soc Nephrol,2009, 20:2493-502
[28]Lloberas N, Cruzado JM, Franquesa M, et al. Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease. J Am Soc Nephrol, 2006, 17:1395-404
[29]Sataranatarajan K, Mariappan MM, Lee MJ, et al.Regulation of elongation phase of mRNA translation in diabetic nephropathy:amelioration by rapamycin. Am J Pathol, 2007, 171:1733-42
[30]Das F, Ghosh-Choudhury N, Venkatesan B, et al. PDGF receptor-βuses Akt/mTORC1 signaling node to promote high glucose-induced renal proximal tubular cell collagen I(α2)expression. Am J Physiol Renal Physiol, 2017, 313:F291-307
[31]Kim SM, Lee SH, Lee A, et al. Targeting T helper 17 by mycophenolate mofetil attenuates diabetic nephropathy progression. Transl Res, 2015, 166:375-83
[32]Yu R, Bo H, Villani V, et al. The inhibitory effect of rapamycin on toll like receptor 4 and interleukin 17 in the early stage of rat diabetic nephropathy. Kidney Blood Press Res, 2016, 41:55-69
[33]Tang Y, Fung E, Xu A, et al. C-reactive protein and ageing. Clin Exp Pharmacol Physiol, 2017, 44:Suppl 1:9-14
[34]Fan W, Han D, Sun Z, et al. Endothelial deletion of mTORC1 protects against hindlimb ischemia in diabetic mice via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation. Free Rad Biomed,2017, 108:725-40
[35]Sivertsson E, Friederich-Persson M,?berg CM, et al.Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability. Am J Physiol Renal Physiol, 2018, 314:F864-72
[2]YuanCM,NeeR,CeckowskiKA,etal.Diabetic nephropathy as the cause of end-stage kidney disease reported on the medical evidence form CMS2728 at a single center. Clin Kidney J, 2017, 10:257-62
[3]Lee EJ, Kang MK, Kim DY. Chrysin inhibits advanced glycation end products-induced kidney fibrosis in renal mesangial cells and diabetic kidneys. Nutrients, 2018, 10:882
[4]Han P, Zhan H, Shao M, et al. Niclosamide ethanolamine improves kidney injury in db/db mice. Diabetes Res Clin Pract, 2018, 144:25-33
[5]Yang H, Jiang X, Li B, et al. Structural mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.Nature, 2017, 552:368-73
[6]Benavides-Serrato A, Lee J, Holmes B, et al. Specific blockade of Rictor-mTOR association inhibits mTORC2activity and is cytotoxic in glioblastoma, 2017, 12:E1176
[7]Dibble CC, Elis W, Menon S, et al. TBC1D7 is a third subunitofthe TSC1-TSC2complexupstreamof mTORC1. Mol Cell, 2012, 47:535-46
[8]Peng H, Kasada A, Ueno M, et al. Distinct roles of Rheb and raptor in activating mTOR complex 1 for the selfrenewal of hematopoietic stem cells. Biochem Biophys Res Commun, 2018, 495:1129-35
[9]Yang G, Murashige DS, Humphrey SJ, et al. A positive feedback loop between Akt and mTORC2 via SIN1phosphorylation. Cell Rep, 2015, 12:937-43
[10]Bera A, Das F, Ghosh-Choudhury N, et al. Reciprocal regulation of miR-214 and PTEN by high glucose regulates renal glomerular mesangial and proximal tubular epithelial cell hypertrophy and matrix expansion. Am J Physiol Cell Physiol, 2017, 313:C430-47
[11]Han F, Xue M, Chang Y, et al. Triptolide suppresses glomerular mesangial cell proliferation in diabetic nephropathy is associated with inhibition of PDK1/Akt/mTOR pathway. Int J Biol Sci, 2017, 13:1266-75
[12]Chen J, Zhao D, Zhu M, et al. Paeoniflorin ameliorates AGEs-induced mesangial cell injury through inhibiting RAGE/mTOR/autophagy pathway. Biomed Pharmacother,2017, 89:1362-9
[13]Das F, Ghosh-Choudhury N, Mariappan MM, et al.Hydrophobic motif site-phosphorylated protein kinase CII between mTORC2 and Akt regulates high glucose-induced mesangial cell hypertrophy. Am J Physiol Cell Physiol,2016, 310:C583-96
[14]Sha W, Shen L, Zhou L, et al. Silencing of CXCL12performs a protective effect on C5b-9-induced injury in podocytes. Int Urol Nephrol, 2018, 50:1535-44
[15]G?del M, Hartleben B, Herbach N, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest, 2011, 121:2197-209
[16]Han P,Shao M,Guo L, et al. Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice.Am J Transl Res, 2018, 10:1071-84
[17]Park JM, Jung CH, Seo M, et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14.Autophagy, 2016, 12:547-64
[18]Yang D, Livingston MJ, Liu Z, et al. Autophagy in diabetic kidney disease:regulation, pathological role and therapeutic. Cell Mol Life Sci, 2018, 75:669-88
[19]Tu Y, Gu L, Chen D, et al. Rhein inhibits autophagy in rat renaltubularcellsbyregulationof AMPK/mTOR signaling. Sci Rep, 2017, 7:43790
[20]Yamahara K, Kume S, Koya D, et al. Obesity-mediated autophagy insufciency exacerbates proteinuria-induced tubulointerstitial lesions. J Am Soc Nephrol, 2013, 24:1769-81
[21]Cin DP, Onay T, Paltoo A, et al. Inhibition of mTOR disrupts autophagic flux in podocytes. J Am Soc Nephrol,2012, 23:412-20
[22]Liu Y, Zhang J, Wang Y, et al. Apelin involved in progressionofdiabeticnephropathybyinhibiting autophagy in podocyte. Cell Death Dis, 2017, 8:e3006
[23]Xiao T, Guan X, Nie L, et al. Rapamycin promotes podocyte autophagy and ameliorates renal injury in diabetic mice. Mol Cell Biochem, 2014, 394:145-54
[24]Wang X, Gao L, Lin H, et al. Mangiferin prevents diabetic nephropathy progression and protects podocyte function via autophagy in diabetic rat glomeruli. Eur J Pharmacol,2018, 824:170-8
[25]Eid S, Boutary S, Braych K, et al. mTORC2 signaling regulates nox4-induced podocyte depletion in diabetes.Antioxid Redox Signal, 2016, 25:703-19
[26]Mariappan MM, Feliers D, Mummidi S, et al. High glucose, high insulin, and their combination rapidly induce laminin-beta1 synthesis by regulation of mRNA translation in renal epithelial cells. Diabetes. 2007, 56:476-85
[27]Lieberthal W, Levine JS. The role of the mammalian target of rapamycin(mTOR)in renal disease. J Am Soc Nephrol,2009, 20:2493-502
[28]Lloberas N, Cruzado JM, Franquesa M, et al. Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease. J Am Soc Nephrol, 2006, 17:1395-404
[29]Sataranatarajan K, Mariappan MM, Lee MJ, et al.Regulation of elongation phase of mRNA translation in diabetic nephropathy:amelioration by rapamycin. Am J Pathol, 2007, 171:1733-42
[30]Das F, Ghosh-Choudhury N, Venkatesan B, et al. PDGF receptor-βuses Akt/mTORC1 signaling node to promote high glucose-induced renal proximal tubular cell collagen I(α2)expression. Am J Physiol Renal Physiol, 2017, 313:F291-307
[31]Kim SM, Lee SH, Lee A, et al. Targeting T helper 17 by mycophenolate mofetil attenuates diabetic nephropathy progression. Transl Res, 2015, 166:375-83
[32]Yu R, Bo H, Villani V, et al. The inhibitory effect of rapamycin on toll like receptor 4 and interleukin 17 in the early stage of rat diabetic nephropathy. Kidney Blood Press Res, 2016, 41:55-69
[33]Tang Y, Fung E, Xu A, et al. C-reactive protein and ageing. Clin Exp Pharmacol Physiol, 2017, 44:Suppl 1:9-14
[34]Fan W, Han D, Sun Z, et al. Endothelial deletion of mTORC1 protects against hindlimb ischemia in diabetic mice via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation. Free Rad Biomed,2017, 108:725-40
[35]Sivertsson E, Friederich-Persson M,?berg CM, et al.Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability. Am J Physiol Renal Physiol, 2018, 314:F864-72