成纤维细胞生长因子23与Klotho在血管钙化相关性的研究进展
|
摘要
本文介绍了血管钙化是导致CKD患者心血管事件的发病率和死亡率增加的主要原因,通过骨矿物质代谢紊乱及炎症在CKD患者中促进血管钙化,提高心血管疾病的风险。而成纤维细胞生长因子23(fibroblast growth factor23,FGF23)及Klotho在CKD患者中可以影响血磷水平,通过回顾这两者对于血磷在肠道的吸收、骨动员、肾脏的代谢的影响,分析其对于CKD患者血管钙化的影响,指出FGF23和Klotho成为研究血管钙化发展的标志物的可能性,是否可以成为早期诊断肾功能不全和预测慢性并发症的新的诊断靶点,提高其临床实用性及经济效益。
This article stated that, vascular calcification might be the main cause for incidence and mortality of cardiovascular events in chronic kidney disease(CKD) patients; through bone mineral metabolism disorder and inflammation, vascular calcification was promoted in CKD patients to increase the risk of cardiovascular diseases; and fibroblast growth factor 23(FGF23) and Klotho could affect the level of blood phosphorus in CKD patients. By reviewing their effects on intestinal absorption, bone mobilization and renal metabolism, their effect on vascular calcification in CKD patients was analyzed. The author pointed out the possibility that FGF23 and Klotho might be the biomarkers for progression of vascular calcification. Finally, it was concluded that they might be new targets for early diagnosis of renal insufficiency and chronic complications, so as to improve their clinical practicality and economic benefits.
This article stated that, vascular calcification might be the main cause for incidence and mortality of cardiovascular events in chronic kidney disease(CKD) patients; through bone mineral metabolism disorder and inflammation, vascular calcification was promoted in CKD patients to increase the risk of cardiovascular diseases; and fibroblast growth factor 23(FGF23) and Klotho could affect the level of blood phosphorus in CKD patients. By reviewing their effects on intestinal absorption, bone mobilization and renal metabolism, their effect on vascular calcification in CKD patients was analyzed. The author pointed out the possibility that FGF23 and Klotho might be the biomarkers for progression of vascular calcification. Finally, it was concluded that they might be new targets for early diagnosis of renal insufficiency and chronic complications, so as to improve their clinical practicality and economic benefits.
引文
[1] Hu MC,Shi M,Gillings N,et al.Recombinant alpha-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy[J].Kidney Int,2017,91(5):1104-1114.
[2] Yamashita H,Yamashita T,Miyamoto M,et al.Fibroblast growth factor (FGF)-23in patients with primary hyperparathyroidism[J].Eur J Endocrinol,2004,151(1):55-60.
[3] Dhayat NA,Ackermann D,Pruijm M,et al.Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function[J].Kidney Int,2016,90(3):648-657.
[4] Schiavi SC,Kumar R.The phosphatonin pathway:new insights in phosphate homeostasis[J].Kidney Int,2004,65(1):1-14.
[5] Scialla JJ,Wolf M.Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease[J].Nat Rev Nephrol,2014,10(5):268-278.
[6] Hu MC,Shiizaki K,Kuro-o M,et al.Fibroblast growth factor 23 and Klotho:physiology and pathophysiology of an endocrine network of mineral metabolism[J].Annu Rev Physiol,2013,75(1):503-533.
[7] Chen G,Liu Y,Goetz R,et al.a-Klotho is a non-enzymatic molecular scaffold for FGF23 hormonesignalling[J].Nature,2018,553(7689):461-466.
[8] Shimada T,Hasegawa H,Yamazaki Y,et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis[J].J Bone Miner Res,2004,19(3):429-435.
[9] Hu MC,Shi M,Zhang J,et al.Klotho:a novelphosphaturic substance acting as an autocrine enzyme in the renal proximal tubule[J].FASEB J,2010,24(9):3438-3450.
[10] Farrow EG,Davis SI,Summers LJ,et al.Initial FGF23-mediated signaling occurs in the distal convoluted tubule[J].J Am Soc Nephrol,2009,20(5):955-960.
[11] Ide N,Olauson H,Sato T,et al.In vivo evidence for a limited role of proximal tubular Klotho in renal phosphate handling[J].Kidney Int,2016,90(2):348-362.
[12] Lu X,Hu MC.Klotho/FGF23 axis in chronic kidney disease and cardiovascular disease[J].Kidney Dis(Basel),2017,3(1):15-23.
[13] Hum JM,O’Brvan LM,Tatiparthi AK,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.
[14] Forster RE,Jurutka PW,Hsieh JC,et al.Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells[J].Biochem Biophys Res Commun,2011,414(3):557-562.
[15] Mitobe M,Yoshida T,Sugiura H,et al.Oxidative stress decreases klotho expression in a mouse kidney cell line[J].Nephron Exp Nephrol,2005,101(2):e67-74.
[16] Wolf MT,An SW,Nie M,et al.Klotho up-regulates renal calcium channel transient receptor potential vanilloid 5 (TRPV5) by intra- and extracellular N-glycosylation-dependent mechanisms[J].J Biol Chem,2014,289(52):35849-35857.
[17] Pavlatou MG,Remaley AT,Gold PW.Klotho:a humeral mediator in CSF and plasma that influences longevity and susceptibility to multiple complex disorders,including depression[J].Transl Psychiatry,2016,6( 8) :e876.
[18] Blau JE,Collins MT.The PTH-Vitamin D-FGF23 axis[J].Rev Endocr Metab Disord,2015,16(2):165-174.
[19] Yoshida T,Fujimori T,Nabeshima Y.Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene[J].Endocrinology,2002,143(2):683-689.
[20] Forster RE,Jurutka PW,Hsieh JC,et al.Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells[J].Biochem Biophys Res Commun,2011,414( 3) :557-562.
[21] Hruska KA,Sugatani T,Agapova O,et al.The chronic kidney disease - Mineral bone disorder(CKD-MBD):Advances in pathophysiology[J].Bone,2017,100:80-86.
[22] Kim JH,Hwang KH,Park KS,et al.Biological role of anti-aging protein Klotho[J].J Lifestyle Med,2015,5(1) :1-6.
[23] Maekawa Y,Ohishi M,Ikushima M,et al.Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway[J].Geriatr Gerontol Int,2011,11(4):510-516.
[24] Haruna Y,Kashihara N,Satoh M,et al.Amelioration of progressive renal injury by genetic manipulation of Klotho gene[J].Proc Natl Acad Sci USA,2007 ,104(7):2331-2336.
[25] Sugiura H,Yoshida T,Mitobe M,et al.Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70[J].Nephrol Dial Transplant,2010,25(1):60-68.
[26] Jono S,McKee MD,Murry CE,et al.Phosphate regulation of vascular smooth muscle cell calcification[J].Circ Res,2000,87(7):E10-17.
[27] Chavkin NW,Chia JJ,Crouthamel MH,et al.Phosphate uptake-independent signaling functions of the type III sodium-dependent phosphate transporter,PiT-1,in vascular smooth muscle cells[J].Exp Cell Res,2015,333(1):39-48.
[28] Shanahan CM,Crouthamel MH,Kapustin A,et al.Arterial calcification in chronic kidney disease:key roles for calcium and phosphate[J].Circ Res,2011,109(6):697-711.
[29] Wallingford MC,Chia J,et al.SLC20A2 deficiency in mice leads to elevated phosphate levels in cerbrospinal fluid and glymphatic pathway-associated arteriolar calcification,and recapitulates human idiopathic basal ganglia calcification[J].Brain Pathol,2017,27(1):64-76.
[30] Giachelli CM.The emerging role of phosphate in vascular calcification[J].Kidney Int,2009,75(9):890-897.
[31] Paloian NJ,Giachelli CM.A current understanding of vascular calcification in CKD[J].Am J Physiol Renal Physiol,2014,307(8):F891-900.
[32] Esapa CT,Hannan FM,Babinsky VN,et al.N-ethyl-N-Nitrosourea ( ENU) induced mutations within the klotho gene lead to ectopic calcification and reduced lifespan in mouse models[J].PLoS One,2015,10(4) :e0122650.
[33] Zeng Y,Wang PH,Zhang M,et al.Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice[J].Aging Clin Exp Res,2016,28(1) :69-76.
[34] Lim K,LuT S,Molostvov G,et al.Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to FGF-23[J].Circulation,2012,125(18) :2243-2255.
[35] Hu MC,Shi M,Cho HJ,et al.Klotho and phosphate are modulators of pathologic uremic cardiac remodeling[J].J Am Soc Nephrol,2015,26(6):1290-1302.
[36] Shi M,Flores B,Gillings N,et al.αKlotho mitigates progression of AKI to CKD through activation of autophagy[J].J Am Soc Nephrol,2016,27(8):2331-2345.
[37] Barker SL,Pastor J,Carranza D,et al.The demonstration of αKlotho deficiency in human chronic kidney disease with a novel synthetic antibody[J].Nephrol Dial Transplant,2015,30 (2):223-233.
[38] Zhang W,Xue D,Hu D,et al.Secreted klotho protein attenuates osteogenic differentiation of human bone marrow mesenchymal stem cells in vitro via inactivation of the FGFR1/ERK signaling pathway[J].Growth factors,2015,33(5-6):356-365.
[39] Chang JR,Guo J,Wang Y,et al.Intermedin1-53 attenuates vascular calcification in rats with chronic kidney disease by upregulation of alpha-Klotho[J].Kidney Int,2016,89(3):586-600.
[2] Yamashita H,Yamashita T,Miyamoto M,et al.Fibroblast growth factor (FGF)-23in patients with primary hyperparathyroidism[J].Eur J Endocrinol,2004,151(1):55-60.
[3] Dhayat NA,Ackermann D,Pruijm M,et al.Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function[J].Kidney Int,2016,90(3):648-657.
[4] Schiavi SC,Kumar R.The phosphatonin pathway:new insights in phosphate homeostasis[J].Kidney Int,2004,65(1):1-14.
[5] Scialla JJ,Wolf M.Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease[J].Nat Rev Nephrol,2014,10(5):268-278.
[6] Hu MC,Shiizaki K,Kuro-o M,et al.Fibroblast growth factor 23 and Klotho:physiology and pathophysiology of an endocrine network of mineral metabolism[J].Annu Rev Physiol,2013,75(1):503-533.
[7] Chen G,Liu Y,Goetz R,et al.a-Klotho is a non-enzymatic molecular scaffold for FGF23 hormonesignalling[J].Nature,2018,553(7689):461-466.
[8] Shimada T,Hasegawa H,Yamazaki Y,et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis[J].J Bone Miner Res,2004,19(3):429-435.
[9] Hu MC,Shi M,Zhang J,et al.Klotho:a novelphosphaturic substance acting as an autocrine enzyme in the renal proximal tubule[J].FASEB J,2010,24(9):3438-3450.
[10] Farrow EG,Davis SI,Summers LJ,et al.Initial FGF23-mediated signaling occurs in the distal convoluted tubule[J].J Am Soc Nephrol,2009,20(5):955-960.
[11] Ide N,Olauson H,Sato T,et al.In vivo evidence for a limited role of proximal tubular Klotho in renal phosphate handling[J].Kidney Int,2016,90(2):348-362.
[12] Lu X,Hu MC.Klotho/FGF23 axis in chronic kidney disease and cardiovascular disease[J].Kidney Dis(Basel),2017,3(1):15-23.
[13] Hum JM,O’Brvan LM,Tatiparthi AK,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.
[14] Forster RE,Jurutka PW,Hsieh JC,et al.Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells[J].Biochem Biophys Res Commun,2011,414(3):557-562.
[15] Mitobe M,Yoshida T,Sugiura H,et al.Oxidative stress decreases klotho expression in a mouse kidney cell line[J].Nephron Exp Nephrol,2005,101(2):e67-74.
[16] Wolf MT,An SW,Nie M,et al.Klotho up-regulates renal calcium channel transient receptor potential vanilloid 5 (TRPV5) by intra- and extracellular N-glycosylation-dependent mechanisms[J].J Biol Chem,2014,289(52):35849-35857.
[17] Pavlatou MG,Remaley AT,Gold PW.Klotho:a humeral mediator in CSF and plasma that influences longevity and susceptibility to multiple complex disorders,including depression[J].Transl Psychiatry,2016,6( 8) :e876.
[18] Blau JE,Collins MT.The PTH-Vitamin D-FGF23 axis[J].Rev Endocr Metab Disord,2015,16(2):165-174.
[19] Yoshida T,Fujimori T,Nabeshima Y.Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene[J].Endocrinology,2002,143(2):683-689.
[20] Forster RE,Jurutka PW,Hsieh JC,et al.Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells[J].Biochem Biophys Res Commun,2011,414( 3) :557-562.
[21] Hruska KA,Sugatani T,Agapova O,et al.The chronic kidney disease - Mineral bone disorder(CKD-MBD):Advances in pathophysiology[J].Bone,2017,100:80-86.
[22] Kim JH,Hwang KH,Park KS,et al.Biological role of anti-aging protein Klotho[J].J Lifestyle Med,2015,5(1) :1-6.
[23] Maekawa Y,Ohishi M,Ikushima M,et al.Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway[J].Geriatr Gerontol Int,2011,11(4):510-516.
[24] Haruna Y,Kashihara N,Satoh M,et al.Amelioration of progressive renal injury by genetic manipulation of Klotho gene[J].Proc Natl Acad Sci USA,2007 ,104(7):2331-2336.
[25] Sugiura H,Yoshida T,Mitobe M,et al.Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70[J].Nephrol Dial Transplant,2010,25(1):60-68.
[26] Jono S,McKee MD,Murry CE,et al.Phosphate regulation of vascular smooth muscle cell calcification[J].Circ Res,2000,87(7):E10-17.
[27] Chavkin NW,Chia JJ,Crouthamel MH,et al.Phosphate uptake-independent signaling functions of the type III sodium-dependent phosphate transporter,PiT-1,in vascular smooth muscle cells[J].Exp Cell Res,2015,333(1):39-48.
[28] Shanahan CM,Crouthamel MH,Kapustin A,et al.Arterial calcification in chronic kidney disease:key roles for calcium and phosphate[J].Circ Res,2011,109(6):697-711.
[29] Wallingford MC,Chia J,et al.SLC20A2 deficiency in mice leads to elevated phosphate levels in cerbrospinal fluid and glymphatic pathway-associated arteriolar calcification,and recapitulates human idiopathic basal ganglia calcification[J].Brain Pathol,2017,27(1):64-76.
[30] Giachelli CM.The emerging role of phosphate in vascular calcification[J].Kidney Int,2009,75(9):890-897.
[31] Paloian NJ,Giachelli CM.A current understanding of vascular calcification in CKD[J].Am J Physiol Renal Physiol,2014,307(8):F891-900.
[32] Esapa CT,Hannan FM,Babinsky VN,et al.N-ethyl-N-Nitrosourea ( ENU) induced mutations within the klotho gene lead to ectopic calcification and reduced lifespan in mouse models[J].PLoS One,2015,10(4) :e0122650.
[33] Zeng Y,Wang PH,Zhang M,et al.Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice[J].Aging Clin Exp Res,2016,28(1) :69-76.
[34] Lim K,LuT S,Molostvov G,et al.Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to FGF-23[J].Circulation,2012,125(18) :2243-2255.
[35] Hu MC,Shi M,Cho HJ,et al.Klotho and phosphate are modulators of pathologic uremic cardiac remodeling[J].J Am Soc Nephrol,2015,26(6):1290-1302.
[36] Shi M,Flores B,Gillings N,et al.αKlotho mitigates progression of AKI to CKD through activation of autophagy[J].J Am Soc Nephrol,2016,27(8):2331-2345.
[37] Barker SL,Pastor J,Carranza D,et al.The demonstration of αKlotho deficiency in human chronic kidney disease with a novel synthetic antibody[J].Nephrol Dial Transplant,2015,30 (2):223-233.
[38] Zhang W,Xue D,Hu D,et al.Secreted klotho protein attenuates osteogenic differentiation of human bone marrow mesenchymal stem cells in vitro via inactivation of the FGFR1/ERK signaling pathway[J].Growth factors,2015,33(5-6):356-365.
[39] Chang JR,Guo J,Wang Y,et al.Intermedin1-53 attenuates vascular calcification in rats with chronic kidney disease by upregulation of alpha-Klotho[J].Kidney Int,2016,89(3):586-600.