二甲双胍通过AMPK信号通路对糖尿病肾脏疾病的保护作用
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摘要
DKD是糖尿病微血管并发症之一,腺苷酸活化蛋白激酶(AMPK)/哺乳动物雷帕霉素靶蛋白信号通路、氧化应激、内质网应激、上皮间质转化、炎症和足细胞IR等参与DKD的发生发展。二甲双胍作为一线口服降糖药,除降糖作用外,也作为AMPK激活剂,通过激活AMPK信号通路干预上述DKD的病理发展过程,从而发挥肾脏保护作用,延缓DKD的发生发展。本文就二甲双胍通过AMPK信号通路对DKD的保护作用机制作简要综述。
DKD is one of the microvascular complications of diabetes. AMP-activated protein kinase(AMPK)/mammalian target of rapamycin signaling pathway,oxidative stress,endoplasmic reticulum stress,epithelithelial-to-mesenchmal transition,inflammation and podocyte insulin resistance(IR)are involved in the development of DKD. Metformin is a first-line oral hypoglycemic agent. In addition to hypoglycemic effect,it also plays as an AMPK activator,interferes with the pathological development of DKD by activating the AMPK signaling pathway. Metformin plays a protective role in the kidney and delays the occurrence and development of DKD. Here,we briefly reviewed the DKD protection mechanism of metformin by AMPK signaling pathway.
DKD is one of the microvascular complications of diabetes. AMP-activated protein kinase(AMPK)/mammalian target of rapamycin signaling pathway,oxidative stress,endoplasmic reticulum stress,epithelithelial-to-mesenchmal transition,inflammation and podocyte insulin resistance(IR)are involved in the development of DKD. Metformin is a first-line oral hypoglycemic agent. In addition to hypoglycemic effect,it also plays as an AMPK activator,interferes with the pathological development of DKD by activating the AMPK signaling pathway. Metformin plays a protective role in the kidney and delays the occurrence and development of DKD. Here,we briefly reviewed the DKD protection mechanism of metformin by AMPK signaling pathway.
引文
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[3]Guo YN,Wang JC,Cai GY,et al.AMPK-mediated downregulation of connexin43 and prematuresenescence of mesangial cells un-der high-glucose conditions.Exp Gerontol,2014,51:71-81.
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[8]Xiao B,Sanders MJ,Underwood E,et al.Structure of mammalian AMPK and its regulation by ADP.Nature,2011,472:230-233.
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[13]Kim H,Moon SY,Kim JS,et al.Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis.Am J Physiol Renal Physiol,2015,308:226-236.
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[25]Wei M,Li Z,Yang Z,et al.Crosstalk between protectiveautophagy and NF-kappaB signal in high glucose-inducedpodocytes.Mol Cell Biochem,2014,394:261-273.
[26]Langer S,Kreutz R,Eisenreich A.Metformin modulates apoptosis and cell signaling of humanpodocytes under high glucose condi-tions.J Nephrol,2016,29:765-773.
[27]Piwkowska A,Rogacka D,Jankowski M,et al.Metformin induces suppression of NAD(P)H oxidase activity in podocytes.Bio-chem Biophys Res Commun,2010,393:268-273.
[28]D’Agati V,Yan SF,Ramasamy R,et al.RAGE,glomerulosclerosis and proteinuria:roles in podocytes and endothelial cells.Trends Endocrinol Metab,2010,21:50-56.
[29]Reiniger N,Lau K,McCalla D,et al.Deletion of the receptor for advanced glycation end products reduces glomerulosclerosisand preserves renal function in the diabetic OVE26 mouse.Diabetes,2010,59:2043-2054.
[30]Ishibashi Y,Matsui T,Takeuchi M,et al.Metformin inhibits advanced glycation endproducts(AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via re-ducing receptor for AGEs(RAGE)expression.Horm Metab Res,2012,44:891-895.
[31]Sharma D,Bhattacharya P,Kana K,et al.Diabetic nephropathy:newinsights into established therapeutic paradigms and novel mo-lecular targets.Diabetes Res Clin Pract,2017,128:91-108.
[32]Lee EK,Jeong JU,Chang JW,et al.Activation of AMP-activated protein kinaseinhibits albumin-induced endoplasmic reticulum-stress and apoptosis through inhibition ofreactive oxygen species.Nephron Exp Nephrol,2012,121:38-48.
[33]He J,Xu Y,Koya D,et al.Role of the endothelial-to-mesenchymal transition in renal fibrosis of chronic kidney disease.Clin Exp Nephrol,2013,17:488-497.
[34]Meran S,Steadman R.Fibroblasts and myofibroblasts in renal fibrosis.Int J Exp Pathol,2011,92:158-167.
[35]Lee JH,Kim JH,Kim JS,et al.AMP-activated protein kinase inhibits TGF-β,angiotensin II,aldosterone,highglucose and albu-min-induced epithelial-mesenchymal transition.Am J Physiol Re-nal Physiol,2013,304:F686-F697.
[36]Cavaglieri RC,Day RT,Feliers D,et al.Metformin prevents renal interstitial fibrosisin mice with unilate ralureteral obstruction.Mol Cell Endocrinol,2015,412:116-122.
[37]Said E,Zaitone SA,Eldosoky M,et al.Nifuroxazide,a STAT3inhibitor,mitigates inflammatory burden and protects against dia-betes-induced nephropathy in rats.Chem Biol Interact,2018,281:111-120.
[38]Ortiz-Mu?oz G,Lopez-Parra V,Lopez-Franco O,et al.Suppressors of cytokinesignaling abrogate diabetic nephropathy.J Am Soc Nephrol,2010,21:763-772.
[39]Xie R,Zhang H,Wang XZ,et al.The protective effect of betulinic acid(BA)diabeticnephropathy on streptozotocin(STZ)-in-duceddiabetic rats.Food Funct,2017,8:299-306.
[40]Welsh GI,Hale LJ,Eremina V,et al.Insulin signaling to the glomerular podocyte is critical for normal kidney function.Cell Metab,2010,12:329-340.
[41]de Kreutzenberg SV,Ceolotto G,Papparella I,et al.Downregulation of the longevity-associated protein sirtuin 1 in insulin resis-tance and metabolic syndrome:potential biochemical mecha-nisms.Diabetes,2010,59:1006-1015.
[42]Hasegawa K,Wakino S,Simic P,et al.Renal tubular Sirt1 attenu-ates diabetic albuminuria by epigenetically suppressing claudin-1overexpression in podocytes.Nat Med,2013,19:1496-1504.
[43]Rogacka D,Piwkowska A,Audzeyenka I,et al.SIRT1-AMPKcrosstalk is involved in high glucose-dependent impairment of in-sulin responsiveness in primary rat podocytes.Exp Cell Res,2016,349:328-338.
[2]Lee MJ,Feliers D,Mariappan MM,et al.A role for AMP-activated protein kinase in diabetes-inducedrenal hypertrophy.Am JPhysiol Renal Physiol,2007,292:617-627.
[3]Guo YN,Wang JC,Cai GY,et al.AMPK-mediated downregulation of connexin43 and prematuresenescence of mesangial cells un-der high-glucose conditions.Exp Gerontol,2014,51:71-81.
[4]Ha TS,Park HY,Nam JA,et al.Diabetic conditions modulate the adenosine monophosphate-activatedprotein kinase of podo-cytes.Kidney Res Clin Pract,2014,33:26-32.
[5]Rogacka D,Audzeyenka I,Rych?owski M,et al.Metformin overcomes high glucose-induced insulin resistance of podocytes by pleiotropic effects on SIRT1 and AMPK.Biochim Biophys Acta,2018,1864:115-125.
[6]Viollet B,Guigas B,Leclerc J,et al.AMP-activated protein kinase in the regulation of hepatic energy metabolism:from physiol-ogy to therapeutic perspectives.Acta Physiol,2009,196:81-98.
[7]Oakhill JS,Steel R,Chen ZP,et al.AMPK Is a direct adenylate charge-regulated protein kinase.Science,2011,332:1433-1435.
[8]Xiao B,Sanders MJ,Underwood E,et al.Structure of mammalian AMPK and its regulation by ADP.Nature,2011,472:230-233.
[9]Zhang BB,Zhou G,Li C.AMPK:an emerging drug target for diabetes and the metabolic syndrome.Cell Metab,2009,9:407-416.
[10]Rogacka D,Piwkowska A,Audzeyenka I,et al.Involvement of the AMPK-PTEN pathway in insulin resistanceinduced by high glucose in cultured rat podocytes.Int J Biochem Cell Biol,2014,51:120-130.
[11]Eid AA,Ford BM,Bhandary B,et al.Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in diabetic re-nal injury.Diabetes,2013,62:2935-2947.
[12]Kidokoro K,Satoh M,Channon KM,et al.Maintenance of endo-thelial guanosine triphosphat cyclohydrolase i ameliorates diabetic nephropathy.J Am Soc Nephrol,2013,24:1139-1150.
[13]Kim H,Moon SY,Kim JS,et al.Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis.Am J Physiol Renal Physiol,2015,308:226-236.
[14]Luo X,Deng L,Lamsal LP,et al.AMP-activated protein kinase alleviates extracellular matrix accumulation in high glucose-in-duced renal fibroblasts through mTOR signaling pathway.Cell Physiol Biochem,2015,35:191-200.
[15]Kim J,Shon E,Kim CS,et al.Renal podocyte injury in a rat model of type 2 diabetes is prevented by Metformin.Exp Diabe-tes Res,2012,2012:210821.
[16]Zhai LM,Gu JF,Yang D,et al.Metformin ameliorates podocyte damage by restoring renal tissue nephrin expression in type 2 dia-betic rats.J Diabetic,2017,9:510-517.
[17]Alhaider AA,Korashy HM,Sayed-Ahmed MM,et al.Metformin attenuates streptozotocin-induced diabetic nephropathy in rats through modulation of oxidative stress genes expression.Chem Bi-ol Interact,2011,192:233-242.
[18]Louro TM,Matafome PN,Nunes EC,et al.Insulin and metformin may prevent renal injury in young type 2 diabetic goto-kak-izaki rats.Eur J Pharmacol,2011,653:89-94.
[19]Arya A,Aggarwal S,Yadav HN.Pathogenesis of diabetic nephropathy.Int J Pharm Sci,2010,2:24-29.
[20]Poplawski MM,Mastaitis JW,Isoda F,et al.Reversal of diabetic nephropathy by aketogenic diet.PLoS One,2011,6:e18604.
[21]Satriano J,Mansoury H,Deng A,et al.Transition of kidneytubule cells to a senescent phenotype in early experimental diabetes.Am J Physiol Cell Physiol,2010,299:374-380.
[22]Lee MJ,Feliers D,Mariappan MM,et al.A role for AMP-activated protein kinase In diabetic-induced renal hypertrophy.Am JPhysiol Renal Physiol,2007,292:617-627.
[23]Molnar Z,Millward AB,Tse W,et al.p21WAF1/CIP1 expression is differentially regulated by Metformin and rapamycin.Int JChronic Dis,2014,2014:327640.
[24]Guo YN,Wang JC,Cai GY,et al.AMPK-mediated downregulation of connexin 43 and prematuresenescence of mesangial cells under high-glucose conditions.EXP Gerontol,2014,51:71-81.
[25]Wei M,Li Z,Yang Z,et al.Crosstalk between protectiveautophagy and NF-kappaB signal in high glucose-inducedpodocytes.Mol Cell Biochem,2014,394:261-273.
[26]Langer S,Kreutz R,Eisenreich A.Metformin modulates apoptosis and cell signaling of humanpodocytes under high glucose condi-tions.J Nephrol,2016,29:765-773.
[27]Piwkowska A,Rogacka D,Jankowski M,et al.Metformin induces suppression of NAD(P)H oxidase activity in podocytes.Bio-chem Biophys Res Commun,2010,393:268-273.
[28]D’Agati V,Yan SF,Ramasamy R,et al.RAGE,glomerulosclerosis and proteinuria:roles in podocytes and endothelial cells.Trends Endocrinol Metab,2010,21:50-56.
[29]Reiniger N,Lau K,McCalla D,et al.Deletion of the receptor for advanced glycation end products reduces glomerulosclerosisand preserves renal function in the diabetic OVE26 mouse.Diabetes,2010,59:2043-2054.
[30]Ishibashi Y,Matsui T,Takeuchi M,et al.Metformin inhibits advanced glycation endproducts(AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via re-ducing receptor for AGEs(RAGE)expression.Horm Metab Res,2012,44:891-895.
[31]Sharma D,Bhattacharya P,Kana K,et al.Diabetic nephropathy:newinsights into established therapeutic paradigms and novel mo-lecular targets.Diabetes Res Clin Pract,2017,128:91-108.
[32]Lee EK,Jeong JU,Chang JW,et al.Activation of AMP-activated protein kinaseinhibits albumin-induced endoplasmic reticulum-stress and apoptosis through inhibition ofreactive oxygen species.Nephron Exp Nephrol,2012,121:38-48.
[33]He J,Xu Y,Koya D,et al.Role of the endothelial-to-mesenchymal transition in renal fibrosis of chronic kidney disease.Clin Exp Nephrol,2013,17:488-497.
[34]Meran S,Steadman R.Fibroblasts and myofibroblasts in renal fibrosis.Int J Exp Pathol,2011,92:158-167.
[35]Lee JH,Kim JH,Kim JS,et al.AMP-activated protein kinase inhibits TGF-β,angiotensin II,aldosterone,highglucose and albu-min-induced epithelial-mesenchymal transition.Am J Physiol Re-nal Physiol,2013,304:F686-F697.
[36]Cavaglieri RC,Day RT,Feliers D,et al.Metformin prevents renal interstitial fibrosisin mice with unilate ralureteral obstruction.Mol Cell Endocrinol,2015,412:116-122.
[37]Said E,Zaitone SA,Eldosoky M,et al.Nifuroxazide,a STAT3inhibitor,mitigates inflammatory burden and protects against dia-betes-induced nephropathy in rats.Chem Biol Interact,2018,281:111-120.
[38]Ortiz-Mu?oz G,Lopez-Parra V,Lopez-Franco O,et al.Suppressors of cytokinesignaling abrogate diabetic nephropathy.J Am Soc Nephrol,2010,21:763-772.
[39]Xie R,Zhang H,Wang XZ,et al.The protective effect of betulinic acid(BA)diabeticnephropathy on streptozotocin(STZ)-in-duceddiabetic rats.Food Funct,2017,8:299-306.
[40]Welsh GI,Hale LJ,Eremina V,et al.Insulin signaling to the glomerular podocyte is critical for normal kidney function.Cell Metab,2010,12:329-340.
[41]de Kreutzenberg SV,Ceolotto G,Papparella I,et al.Downregulation of the longevity-associated protein sirtuin 1 in insulin resis-tance and metabolic syndrome:potential biochemical mecha-nisms.Diabetes,2010,59:1006-1015.
[42]Hasegawa K,Wakino S,Simic P,et al.Renal tubular Sirt1 attenu-ates diabetic albuminuria by epigenetically suppressing claudin-1overexpression in podocytes.Nat Med,2013,19:1496-1504.
[43]Rogacka D,Piwkowska A,Audzeyenka I,et al.SIRT1-AMPKcrosstalk is involved in high glucose-dependent impairment of in-sulin responsiveness in primary rat podocytes.Exp Cell Res,2016,349:328-338.