Klotho蛋白在糖尿病肾病中的研究进展
|
摘要
糖尿病肾病是糖尿病微血管并发症之一,也是终末期肾衰竭的主要致病因素。作为一种多因素作用下的复杂疾病,多种细胞因子、信号通路等参与其中。现阶段临床上针对糖尿病肾病所导致的高致残率、高死亡率,尚无确切有效的治疗方案,寻找新的治疗靶点,将具有重要的临床价值。Klotho作为一种抗衰老基因,其编码的蛋白具有广泛的生物学效应,在多种急、慢性肾脏病中发挥肾脏保护作用,并与糖尿病肾病的发生发展关系密切。本文将从Klotho参与调节氧化应激、血管钙化、内皮功能紊乱、肾脏纤维化四个方面,探讨其在糖尿病肾病中的作用。
Diabetic nephropathy( DN) is one of microvascular complications of diabetes mellitus and is a leading cause of end-stage renal failure. As a kind of complicated disease,various cytokines and signaling pathways have been shown to mediate renal damage in DN. The optimal treatment for DN remains undefined. Seeking for a novel therapeutic target will be important in treatment of DN. Klotho is an anti-aging protein that exerts its biological functions through multiple modes on different kidney diseases. Klotho is closely associated with the pathogenesis of kidney injury in DN. This article will review its renoprotection effects via 4 kinds of potential mechanisms such as anti-vascular calcification,anti-endothelial dysfuction,anti-oxidative stress and anti-fibrosis.
Diabetic nephropathy( DN) is one of microvascular complications of diabetes mellitus and is a leading cause of end-stage renal failure. As a kind of complicated disease,various cytokines and signaling pathways have been shown to mediate renal damage in DN. The optimal treatment for DN remains undefined. Seeking for a novel therapeutic target will be important in treatment of DN. Klotho is an anti-aging protein that exerts its biological functions through multiple modes on different kidney diseases. Klotho is closely associated with the pathogenesis of kidney injury in DN. This article will review its renoprotection effects via 4 kinds of potential mechanisms such as anti-vascular calcification,anti-endothelial dysfuction,anti-oxidative stress and anti-fibrosis.
引文
[1]SHAW J E,SICREE R A,ZIMMET P Z.Global estimates of the prevalence of diabetes for 2010 and 2030[J].Diabetes Res Clin Pr,2010,87(1):4-14.
[2]KURO-O M,MATSUMURA Y,AIZAWA H,et al.Mutation of the mouse Klotho gene leads to a syndrome resembling ageing[J].Nature,1997,390(6655):45-51.
[3]HU M C,KUROO M,MOE O W.Klotho and kidney disease[J].J Nephrol,2010,23 Suppl 16(4):136-144.
[4]YOSHISUKE H,NAOKI K,MINORU S,et al.Amelioration of progressive renal injury by genetic manipulation of Klotho gene[J].PNAS,2007,104(7):2331-2336.
[5]KOH N,FUJIMORI T,NISHIGUCHI S,et al.Severely reduced production of klotho in human chronic renal failure kidney[J].Biochem Bioph Res Co,2001,280(4):1015-1020.
[6]HIDEKAZU S,TAKUMI Y,KEN T,et al.Klotho reduces apoptosis in experimental ischaemic acute renal failure[J].Nephrol Dial Transpl,2005,20(12):2636-2645.
[7]CHENG M F,CHEN L J,CHENG J T.Decrease of klotho in the kidney of streptozotocin-induced diabetic rats[J].Biomed Res Int,2010:513853.
[8]SUSZTAK K,RAFF A C,SCHIFFER M,et al.Glucoseinduced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy[J].Diabetes,2006,55(1):225-233.
[9]PICONI L,QUAGLIARO L,ASSALONI R,et al.Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction[J].Diabetes-Metab Res,2006,22(3):198-203.
[10]RODRIGUES A M,SERRALHA R S,FARIAS C,et al.P2X 7,receptor and klotho expressions in diabetic nephropathy progression[J].Purinerg Signal,2018,14(2):1-10.
[11]MENZIES R I,BOOTH J W R,MULLINS J J,et al.Hyperglycemia-induced Renal P2X7 Receptor Activation Enhances Diabetes-related Injury[J].Ebiomedicine,2017,19(C):73-83.
[12]YAMAMOTO M,CLARK J D,PASTOR J V,et al.Regulation of oxidative stress by the anti-aging hormone klotho[J].J Biol Chem,2005,280(45):38029-38034.
[13]EMERLING B M,WEINBERG F,LIU J L,et al.PTENregulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor3a(FOXO3a)[J].P Natl Acad Sci USA,2008,105(7):2622-2627.
[14]LIM S W,JIN L,LUO K,et al.Klotho enhances Fox O3-mediated manganese superoxide dismutase expression by negatively regulating PI3K/AKT pathway during tacrolimus-induced oxidative stress[J].Cell Death Dis,2017,8:e2972.
[15]LIU Y N,ZHOU J W,LI T T,et al.Sulodexide protects renal tubular epithelial cells from oxidative stress-induced injury via upregulating klotho expression at an early stage of diabetic kidney disease[J].J Diabetes Res,2017(8):4989847.
[16]HUM J M,O'BRYAN L M,TATIPARTHI A K,et al.Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho[J].J Am Soc Nephrol,2017,28(4):1162-1174.
[17]JONO S,MCKEE M D,MURRY C E,et al.Phosphate regulation of vascular smooth muscle cell calcification[J].Circ Res,2000,87(7):10-17.
[18]HU M C,SHI M J,PASTOR J,et al.Klotho:a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule[J].Faseb J,2010,24(9):3438-3450.
[19]TITAN S M,ZATZ R,GRACIOLLI F G,et al.FGF-23 as a predictor of renal outcome in diabetic nephropathy[J].Clin J Am Soc Nephro,2011,6(2):241-247.
[20]KIM S S,SONG S H,KIM I J,et al.Decreased plasmaα-Klotho predict progression of nephropathy with type 2 diabetic patients[J].J Diabetes Complicat,2016,30(5):887-892.
[21]马春园,郝丽荣.FGF23-Klotho轴在慢性肾脏病骨矿物质代谢紊乱中的作用[J].医学综述,2015,21(7):1169-1172.
[22]LEE E Y,KIM S S,LEE J S,et al.Solubleα-klotho as a novel biomarker in the early stage of nephropathy in patients with type 2 diabetes[J].Plos One,2014,9(8):e102984.
[23]TAKAHASHI H,KOMABA H,TAKAHASHI Y,et al.Impact of parathyroidectomy on serum FGF23 and soluble Klotho in hemodialysis patients with severe secondary hyperparathyroidism[J].J Clin Endocr Metab,2014,99(4):E652-E658.
[24]KUSABA T,OKIGAKI M,MATUI A,et al.Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+channel to maintain endothelial integrity[J].PNAS,2010,107(45):19308-19313.
[25]KACSO I M,BONDOR C I,KACSO G.Soluble serum Klotho in diabetic nephropathy:Relationship to VEGF-A[J].Clin Biochem,2012,45(16/17):1415-1420.
[26]KIDOKORO K,SATOH M,CHANNON K M,et al.Maintenance of endothelial guanosine triphosphate cyclohydrolase I ameliorates diabetic nephropathy[J].J Am Soc Nephrol,2013,24(7):1139-1150.
[27]SALMON A H J,FERGUSON J K,BURFORD J L,et al.Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction[J].J Am Soc Nephrol,2012,23(8):1339-1350.
[28]KADOYA H,SATOH M,HARUNA Y,et al.Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice[J].Clin Exp Nephrol 2016,20(5):671-678.
[29]STALKER T J,SKVARKA C B,SCALIA R.A novel role for calpains in the endothelial dysfunction of hyperglycemia[J].Faseb J,2003,17(11):1511.
[30]MANYA H,INOMATA M,FUJIMORI,et al.Klotho protein deficiency leads to overactivation of mu-calpain[J].JBiol Chem,2002,277(38):35503-35508.
[31]KANWAR Y S,SUN L,XIE P,et al.A Glimpse of Various Pathogenetic Mechanisms of Diabetic Nephropathy[J].Annu Rev Pathol-Mech,2011,6:395-423.
[32]LIN Y,KURO-O M,SUN Z J.Genetic deficiency of antiaging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice[J].Endocrinology,2013,154(10):3855-3863.
[33]XIAO L,WANG M,YANG S,et al.A glimpse of the pathogenetic mechanisms of Wnt/β-catenin signaling in diabetic nephropathy[J].B Biomed Res Int,2013:987064.
[34]ZHOU T,HE X,CHENG R,et al.Implication of dysregulation of the canonical wingless-type MMTV integration site(WNT)pathway in diabetic nephropathy[J].Diabetologia,2012,55(1):255-266.
[35]ZHOU L,LI Y,ZHOU D,et al.Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling[J].J Am Soc Nephrol,2013,24(5):771-785.
[36]胡应林.Klotho基因在糖尿病肾病小鼠模型的表达及肾安颗粒的干预作用[D].武汉:湖北中医药大学,2015.
[37]OH H J,NAM B Y,WU M,et al.Klotho plays a protective role against glomerular hypertrophy in a cell cycle-dependent manner in diabetic nephropathy[J].Am J Physiol-Renal,2018,315(4):F791-F805.
[2]KURO-O M,MATSUMURA Y,AIZAWA H,et al.Mutation of the mouse Klotho gene leads to a syndrome resembling ageing[J].Nature,1997,390(6655):45-51.
[3]HU M C,KUROO M,MOE O W.Klotho and kidney disease[J].J Nephrol,2010,23 Suppl 16(4):136-144.
[4]YOSHISUKE H,NAOKI K,MINORU S,et al.Amelioration of progressive renal injury by genetic manipulation of Klotho gene[J].PNAS,2007,104(7):2331-2336.
[5]KOH N,FUJIMORI T,NISHIGUCHI S,et al.Severely reduced production of klotho in human chronic renal failure kidney[J].Biochem Bioph Res Co,2001,280(4):1015-1020.
[6]HIDEKAZU S,TAKUMI Y,KEN T,et al.Klotho reduces apoptosis in experimental ischaemic acute renal failure[J].Nephrol Dial Transpl,2005,20(12):2636-2645.
[7]CHENG M F,CHEN L J,CHENG J T.Decrease of klotho in the kidney of streptozotocin-induced diabetic rats[J].Biomed Res Int,2010:513853.
[8]SUSZTAK K,RAFF A C,SCHIFFER M,et al.Glucoseinduced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy[J].Diabetes,2006,55(1):225-233.
[9]PICONI L,QUAGLIARO L,ASSALONI R,et al.Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction[J].Diabetes-Metab Res,2006,22(3):198-203.
[10]RODRIGUES A M,SERRALHA R S,FARIAS C,et al.P2X 7,receptor and klotho expressions in diabetic nephropathy progression[J].Purinerg Signal,2018,14(2):1-10.
[11]MENZIES R I,BOOTH J W R,MULLINS J J,et al.Hyperglycemia-induced Renal P2X7 Receptor Activation Enhances Diabetes-related Injury[J].Ebiomedicine,2017,19(C):73-83.
[12]YAMAMOTO M,CLARK J D,PASTOR J V,et al.Regulation of oxidative stress by the anti-aging hormone klotho[J].J Biol Chem,2005,280(45):38029-38034.
[13]EMERLING B M,WEINBERG F,LIU J L,et al.PTENregulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor3a(FOXO3a)[J].P Natl Acad Sci USA,2008,105(7):2622-2627.
[14]LIM S W,JIN L,LUO K,et al.Klotho enhances Fox O3-mediated manganese superoxide dismutase expression by negatively regulating PI3K/AKT pathway during tacrolimus-induced oxidative stress[J].Cell Death Dis,2017,8:e2972.
[15]LIU Y N,ZHOU J W,LI T T,et al.Sulodexide protects renal tubular epithelial cells from oxidative stress-induced injury via upregulating klotho expression at an early stage of diabetic kidney disease[J].J Diabetes Res,2017(8):4989847.
[16]HUM J M,O'BRYAN L M,TATIPARTHI A K,et al.Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho[J].J Am Soc Nephrol,2017,28(4):1162-1174.
[17]JONO S,MCKEE M D,MURRY C E,et al.Phosphate regulation of vascular smooth muscle cell calcification[J].Circ Res,2000,87(7):10-17.
[18]HU M C,SHI M J,PASTOR J,et al.Klotho:a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule[J].Faseb J,2010,24(9):3438-3450.
[19]TITAN S M,ZATZ R,GRACIOLLI F G,et al.FGF-23 as a predictor of renal outcome in diabetic nephropathy[J].Clin J Am Soc Nephro,2011,6(2):241-247.
[20]KIM S S,SONG S H,KIM I J,et al.Decreased plasmaα-Klotho predict progression of nephropathy with type 2 diabetic patients[J].J Diabetes Complicat,2016,30(5):887-892.
[21]马春园,郝丽荣.FGF23-Klotho轴在慢性肾脏病骨矿物质代谢紊乱中的作用[J].医学综述,2015,21(7):1169-1172.
[22]LEE E Y,KIM S S,LEE J S,et al.Solubleα-klotho as a novel biomarker in the early stage of nephropathy in patients with type 2 diabetes[J].Plos One,2014,9(8):e102984.
[23]TAKAHASHI H,KOMABA H,TAKAHASHI Y,et al.Impact of parathyroidectomy on serum FGF23 and soluble Klotho in hemodialysis patients with severe secondary hyperparathyroidism[J].J Clin Endocr Metab,2014,99(4):E652-E658.
[24]KUSABA T,OKIGAKI M,MATUI A,et al.Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+channel to maintain endothelial integrity[J].PNAS,2010,107(45):19308-19313.
[25]KACSO I M,BONDOR C I,KACSO G.Soluble serum Klotho in diabetic nephropathy:Relationship to VEGF-A[J].Clin Biochem,2012,45(16/17):1415-1420.
[26]KIDOKORO K,SATOH M,CHANNON K M,et al.Maintenance of endothelial guanosine triphosphate cyclohydrolase I ameliorates diabetic nephropathy[J].J Am Soc Nephrol,2013,24(7):1139-1150.
[27]SALMON A H J,FERGUSON J K,BURFORD J L,et al.Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction[J].J Am Soc Nephrol,2012,23(8):1339-1350.
[28]KADOYA H,SATOH M,HARUNA Y,et al.Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice[J].Clin Exp Nephrol 2016,20(5):671-678.
[29]STALKER T J,SKVARKA C B,SCALIA R.A novel role for calpains in the endothelial dysfunction of hyperglycemia[J].Faseb J,2003,17(11):1511.
[30]MANYA H,INOMATA M,FUJIMORI,et al.Klotho protein deficiency leads to overactivation of mu-calpain[J].JBiol Chem,2002,277(38):35503-35508.
[31]KANWAR Y S,SUN L,XIE P,et al.A Glimpse of Various Pathogenetic Mechanisms of Diabetic Nephropathy[J].Annu Rev Pathol-Mech,2011,6:395-423.
[32]LIN Y,KURO-O M,SUN Z J.Genetic deficiency of antiaging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice[J].Endocrinology,2013,154(10):3855-3863.
[33]XIAO L,WANG M,YANG S,et al.A glimpse of the pathogenetic mechanisms of Wnt/β-catenin signaling in diabetic nephropathy[J].B Biomed Res Int,2013:987064.
[34]ZHOU T,HE X,CHENG R,et al.Implication of dysregulation of the canonical wingless-type MMTV integration site(WNT)pathway in diabetic nephropathy[J].Diabetologia,2012,55(1):255-266.
[35]ZHOU L,LI Y,ZHOU D,et al.Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling[J].J Am Soc Nephrol,2013,24(5):771-785.
[36]胡应林.Klotho基因在糖尿病肾病小鼠模型的表达及肾安颗粒的干预作用[D].武汉:湖北中医药大学,2015.
[37]OH H J,NAM B Y,WU M,et al.Klotho plays a protective role against glomerular hypertrophy in a cell cycle-dependent manner in diabetic nephropathy[J].Am J Physiol-Renal,2018,315(4):F791-F805.