-
摘要: Klotho基因是高表达于肾脏的一种抗衰老基因,其编码产物Klotho蛋白对肾脏组织的炎症反应、氧化应激损伤及细胞凋亡等具有抑制作用,是一种肾脏保护蛋白,有望成为新的肾脏疾病治疗靶点。本文就Klotho的生物学特点以及Klotho对移植肾功能的保护作用进行综述。Abstract: Klotho gene is an anti-aging gene that is highly expressed in the kidney. Its encoding product Klotho protein can inhibit inflammation, oxidative stress injury, and apoptosis in renal tissue. It is regarded as a renal protective protein and expected to be a new target for the treatment of renal diseases. This article reviewed the biological characteristics of Klotho and the protective effect of Klotho on renal graft function.
-
Key words:
- Klotho /
- Renal transplantation /
- Renal protective protein /
- Aging /
- Inflammation /
- Oxidative stress /
- Apoptosis /
- Renal graft function
-
[1] 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. doi: 10.1038/36285 [2] LIM K, GROEN A, MOLOSTVOV G, et al. α-Klotho expression in human tissues[J]. J Clin Endocrinol Metab, 2015, 100(10): E1308-E1318. DOI: 10.1210/jc.2015-1800. [3] XU Y, SUN Z. Molecular basis of Klotho: from gene to function in aging[J]. Endocr Rev, 2015, 36(2):174-193. DOI: 10.1210/er.2013-1079. [4] URAKAWA I, YAMAZAKI Y, SHIMADA T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23[J]. Nature, 2006, 444(7120):770-774. doi: 10.1038/nature05315 [5] CHEN G, LIU Y, GOETZ R, et al. α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signaling[J]. Nature, 2018, 553(7689):461-466. DOI: 10.1038/nature25451. [6] HU MC, SHI M, MOE OW. Role of αKlotho and FGF23 in regulation of type Ⅱ Na-dependent phosphateco-transporters[J]. Pflugers Arch, 2019, 471(1):99-108. DOI: 10.1007/s00424-018-2238-5. [7] VAN LOON EP, PULSKENS WP, VAN DER HAGEN EA, at al. Shedding of Klotho by ADAMs in the kidney[J]. Am J Physiol Renal Physiol, 2015, 309(4):F359-F368. DOI: 10.1152/ajprenal.00240.2014. [8] HU MC, KURO-O M, MOE OW. Renal and extrarenal actions of Klotho[J]. Semin Nephrol, 2013, 33(2):118-129. DOI: 10.1016/j.semnephrol.2012.12.013. [9] KIM JH, HWANG KH, PARK KS, et al. Biological role of anti-aging protein Klotho[J]. J Lifestyle Med, 2015, 5(1):1-6. DOI: 10.15280/jlm.2015.5.1.1. [10] HU MC, SHI M, ZHANG J, et al. Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective[J]. Kidney Int, 2010, 78(12):1240-1251. DOI: 10.1038/ki.2010.328. [11] 孙敏, 樊恒, 乐健伟, 等. Klotho蛋白对脓毒症急性肾损伤小鼠的肾脏保护作用及其机制研究[J].中华危重病急救医学, 2019, 31(2):160-164. DOI: 10.3760/cma.j.issn.2095-4352.2019.02.008.SUN M, FAN H, LE JW, et al. Protective effects of Klotho protein on acute kidney injury in septic mice and its mechanism[J]. Chin Crit Care Med, 2019, 31(2):160-164. DOI: 10.3760/cma.j.issn.2095-4352.2019.02.008. [12] ZHOU L, MO H, MIAO J, et al. Klotho ameliorates kidney injury and fibrosis and normalizes blood pressure by targeting the renin-angiotensin system[J]. Am J Pathol, 2015, 185(12):3211-3223. DOI: 10.1016/j.ajpath.2015.08.004. [13] CHEN X, TONG H, CHEN Y, et al. Klotho ameliorates sepsis-induced acute kidney injury but is irrelevant to autophagy[J]. Onco Targets Ther, 2018, 11:867-881. DOI: 10.2147/OTT.S156891. [14] OH HJ, OH H, NAM BY, at al. The protective effect of Klotho against contrast-associated acute kidney injury via the antioxidative effect[J]. Am J Physiol Renal Physiol, 2019, 317(4):F881-F889. DOI: 10.1152/ajprenal.00297.2018. [15] KO JW, SHIN NR, JUNG TY, et al. Melatonin attenuates cisplatin-induced acute kidney injury in rats via induction of anti-aging protein, Klotho[J]. Food Chem Toxicol, 2019, 129:201-210. DOI: 10.1016/j.fct.2019.04.049. [16] WANG Q, REN D, LI Y, et al. Klotho attenuates diabetic nephropathyy in db/db mice and ameliorates high glucose-induced injury of human renal glomerular endothelial cells[J]. Cell Cycle, 2019, 18(6/7):696-707. DOI: 10.1080/15384101.2019.1580495. [17] KIM JH, XIE J, HWANG KH, et al. Klotho may ameliorate proteinuria by targeting TRPC6 channels in podocytes[J]. J Am Soc Nephrol, 2017, 28(1):140-151. DOI: 10.1681/ASN.2015080888. [18] HU MC, SHI M, ZHANG 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. DOI: 10.1096/fj.10-154765. [19] OLAUSON H, MENCKE R, HILLEBRANDS JL, et al. Tissue expression and source of circulating αKlotho[J]. Bone, 2017, 100:19-35. DOI: 10.1016/j.bone.2017.03.043. [20] HU MC, SHI M, ZHANG J, et al. Renal production, uptake, and handling of circulating αKlotho[J]. J Am Soc Nephrol, 2016, 27(1):79-90. DOI: 10.1681/ASN.2014101030. [21] TONELLI M, RIELLA MC. World Kidney Day 2014: CKD and the aging population[J]. Am J Kidney Dis, 2014, 63(3):349-353. DOI: 10.1053/j.ajkd.2014.01.003. [22] WEI SY, PAN SY, LI B, et al. Rejuvenation: turning back the clock of aging kidney[J]. J Formos Med Assoc, 2020, 119(5):898-906. DOI: 10.1016/j.jfma.2019.05.020. [23] PAPACONSTANTINOU J. Insulin/IGF-1 and ROS signaling pathway cross-talk in aging and longevity determination[J]. Mol Cell Endocrinol, 2009, 299(1):89-100. DOI: 10.1016/j.mce.2008.11.025. [24] ZUO Z, LEI H, WANG X, et al. Aging-related kidney damage is associated with a decrease in Klotho expression and an increase in superoxide production[J]. Age (Dordr), 2011, 33(3):261-274. DOI: 10.1007/s11357-010-9176-2. [25] YAMAZAKI Y, IMURA A, URAKAWA I, et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: age-dependent change of soluble alpha-Klotho levels in healthy subjects[J]. Biochem Biophys Res Commun, 2010, 398(3):513-518. DOI: 10.1016/j.bbrc. 2010.06.110. [26] LI Z, WANG Z. Aging kidney and aging-related disease[J]. Adv Exp Med Biol, 2018, 1086:169-187. DOI: 10.1007/978-981-13-1117-8_11. [27] STENVINKEL P, LARSSON TE. Chronic kidney disease: a clinical model of premature aging[J]. Am J Kidney Dis, 2013, 62(2):339-351. DOI: 10.1053/j.ajkd.2012.11.051. [28] SEIBERT E, RADLER D, ULRICH C, et al. Serum Klotho levels in acute kidney injury[J]. Clin Nephrol, 2017, 87(4):173-179. DOI: 10.5414/CN108970. [29] DREW DA, KATZ R, KRITCHEVSKY S, et al. Association between soluble Klotho and change in kidney function: the health aging and body composition study[J]. J Am Soc Nephrol, 2017, 28(6):1859-1866. DOI: 10.1681/ASN.2016080828. [30] KIM HR, NAM BY, KIM DW, et al. Circulating α-Klotho levels in CKD and relationship to progression[J]. Am J Kidney Dis, 2013, 61(6):899-909. DOI: 10.1053/j.ajkd.2013.01.024. [31] BLAINE J, CHONCHOL M, LEVI M. Renal control of calcium, phosphate, and magnesium homeostasis[J]. Clin J Am Soc Nephrol, 2015, 10(7):1257-1272. DOI: 10.2215/CJN.09750913. [32] OLAUSON H, LINDBERG K, AMIN R, et al. Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism[J]. J Am Soc Nephrol, 2012, 23(10):1641-1651. doi: 10.1681/ASN.2012010048 [33] MARTÍN-NÚÑEZ E, DONATE-CORREA J, KANNENGIESSER C, et al. A novel heterozygous deletion variant in Klotho gene leading to haploinsufficiency and impairment of fibroblast growth factor 23 signaling pathway[J]. J Clin Med, 2019, 8(4):E500. DOI: 10.3390/jcm8040500. [34] DISTHABANCHONG S. Phosphate and cardiovascular disease beyond chronic kidney disease and vascular calcification[J]. Int J Nephrol, 2018: 3162806. DOI: 10.1155/2018/3162806. [35] LIU Z, ZHOU H, CHEN X, et al. Relationship between cFGF23/Klotho ratio and phosphate levels in patients with chronic kidney disease[J]. Int Urol Nephrol, 2019, 51(3):503-507. DOI: 10.1007/s11255-019-02079-4. [36] CHEN YX, HUANG C, DUAN ZB, et al. Klotho/FGF23 axis mediates high phosphate-induced vascular calcification in vascular smooth muscle cells via Wnt7b/β-catenin pathway[J]. Kaohsiung J Med Sci, 2019, 35(7):393-400. DOI: 10.1002/kjm2.12072. [37] YANG HC, ROSSINI M, MA LJ, et al. Cells derived from young bone marrow alleviate renal aging[J]. J Am Soc Nephrol, 2011, 22(11):2028-2036. DOI: 10.1681/ASN.2010090982. [38] ZHANG F, WAN X, CAO YZ, et al. Klotho gene-modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β-catenin pathway in kidneys after acute injury[J]. Cell Biol Int, 2018, 42(12):1670-1679. DOI: 10.1002/cbin.11068. [39] MELK A, RAMASSAR V, HELMS LM, et al. Telomere shortening in kidneys with age[J]. J Am Soc Nephrol, 2000, 11(3):444-453. doi: 10.1046-j.1523-1755.2003.00032.x/ [40] KIDIR V, AYNALI A, ALTUNTAS A, et al. Telomerase activity in patients with stage 2-5D chronic kidney disease[J]. Nefrologia, 2017, 37(6):592-597. DOI: 10.1016/j.nefro.2017.03.025. [41] DOMAŃSKI L, KŁODA K, KWIATKOWSKA E, et al. Effect of delayed graft function, acute rejection and chronic allograft dysfunction on kidney allograft telomere length in patients after transplantation: a prospective cohort study[J]. BMC Nephrol, 2015, 16:23. DOI: 10.1186/s12882-015-0014-8. [42] ULLAH M, SUN Z. Klotho deficiency accelerates stem cells aging by impairing telomerase activity[J]. J Gerontol A Biol Sci Med Sci, 2019, 74(9):1396-1407. DOI: 10.1093/gerona/gly261. [43] ELTZSCHIG HK, ECKLE T. Ischemia and reperfusion--from mechanism to translation[J]. Nat Med, 2011, 17(11):1391-1401. DOI: 10.1038/nm.2507. [44] KORKMAZ A, KOLANKAYA D. Inhibiting inducible nitric oxide synthase with rutin reduces renal ischemia/reperfusion injury[J]. Can J Surg, 2013, 56(1):6-14. DOI: 10.1503/cjs.004811. [45] SIEDLECKI A, IRISH W, BRENNAN DC. Delayed graft function in the kidney transplant[J]. Am J Transplant, 2011, 11(11):2279-2296. DOI: 10.1111/j.1600-6143.2011. 03754.x. [46] 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. DOI: 10.1093/ndt/gfp451. [47] CASTELLANO G, INTINI A, STASI A, et al. Complement modulation of anti-aging factor Klotho in ischemia/reperfusion injury and delayed graft function[J]. Am J Transplant, 2016, 16(1):325-333. DOI: 10.1111/ajt.13415. [48] QIAN Y, GUO X, CHE L, et al. Klotho reduces necroptosis by targeting oxidative stress involved in renal ischemic-reperfusion injury[J]. Cell Physiol Biochem, 2018, 45(6):2268-2282. DOI: 10.1159/000488172. [49] JIANG S, CHEN Y, ZOU J, et al. Diverse effects of ischemic pretreatments on the long-term renal damage induced by ischemia-reperfusion[J]. Am J Nephrol, 2009, 30(5):440-449. DOI: 10.1159/000239574. [50] ARAUJO M, WELCH WJ. Oxidative stress and nitric oxide in kidney function[J]. Curr Opin Nephrol Hypertens, 2006, 15(1):72-77. doi: 10.1097/01.mnh.0000191912.65281.e9 [51] SHEN Y, YAN Y, LU L, et al. Klotho ameliorates hydrogen peroxide-induced oxidative injury in TCMK-1cells[J]. Int Urol Nephrol, 2018, 50(4):787-798. DOI: 10.1007/s11255-017-1765-x. [52] STROO I, STOKMAN G, TESKE GJ, et al. Chemokine expression in renal ischemia/reperfusion injury is most profound during the reparative phase[J]. Int Immunol, 2010, 22(6):433-442. DOI: 10.1093/intimm/dxq025. [53] KARIN M, YAMAMOTO Y, WANG QM. The IKK NF-kappa B system: a treasure trove for drug development[J]. Nat Rev Drug Discov, 2004, 3(1):17-26. http://onlinelibrary.wiley.com/resolve/reference/PMED?id=14708018 [54] PANAH F, GHORBANIHAGHJO A, ARGANI H, et al. Ischemic acute kidney injury and Klotho in renal transplantation[J]. Clin Biochem, 2018, 55:3-8. DOI: 10.1016/j.clinbiochem.2018.03.022. [55] CRAVEDI P, HEEGER PS. Complement as a multifaceted modulator of kidney transplant injury[J]. J Clin Invest, 2014, 124(6):2348-2354. DOI: 10.1172/JCI72273. [56] LIU L, GAO H, HONG C, et al. Klotho attenuated antibody-mediated porcine endothelial cell activation and injury[J]. Xenotransplantation, 2017, 24(1). DOI: 10.1111/xen.12286. [57] JAIN S, KEYS D, NYDAM T, et al. Inhibition of autophagy increases apoptosis during re-warming after cold storage in renal tubular epithelial cells[J]. Transpl Int, 2015, 28(2):214-223. DOI: 10.1111/tri.12465. [58] 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. DOI: 10.1681/ASN.2015060613. [59] Chinese Society of Organ Transplantation, Chinese Medical Association. National guidelines for donation after cardiac death in China[J]. Hepatobiliary Pancreat Dis Int, 2013, 12(3):234-238. doi: 10.1016/S1499-3872(13)60038-7 [60] SMAIL N, TCHERVENKOV J, PARASKEVAS S, et al. Impact of early graft function on 10-year graft survival in recipients of kidneys from standard- or expanded-criteria donors[J]. Transplantation, 2013, 96(2):176-181. DOI: 10.1097/TP.0b013e318297443b. [61] SEO MY, YANG J, LEE JY, et al. Renal Klotho expression in patients with acute kidney injury is associated with the severity of the injury[J]. Korean J Intern Med, 2015, 30(4):489-495. DOI: 10.3904/kjim.2015.30.4.489. [62] BLESKESTAD IH, THORSEN IS, JONSSON G, et al. Soluble Klotho and intact fibroblast growth factor 23 in long-term kidney transplant patients[J]. Eur J Endocrinol, 2015, 172(4):343-350. DOI: 10.1530/EJE-14-0457. [63] DENG G, YANG A, WU J, et al. The value of older donors' Klotho level in predicting recipients' short-term renal function[J]. Med Sci Monit, 2018, 24:7936-7943. DOI: 10.12659/MSM.913274. [64] KIMURA T, AKIMOTO T, WATANABE Y, et al. Impact of renal transplantation and nephrectomy on urinary soluble Klotho protein[J]. Transplant Proc, 2015, 47(6):1697-1699. DOI: 10.1016/j.transproceed.2015.06.025. [65] JIN M, LV P, CHEN G, et al. Klotho ameliorates cyclosporine A-induced nephropathy via PDLIM2/NF-kB p65 signaling pathway[J]. Biochem Biophys Res Commun, 2017, 486(2):451-457. DOI: 10.1016/j.bbrc.2017.03.061. [66] LIU QF, YE JM, YU LX, et al. Klotho mitigates cyclosporine A (CsA)-induced epithelial-mesenchymal transition (EMT) and renal fibrosis in rats[J]. Int Urol Nephrol, 2017, 49(2):345-352. DOI: 10.1007/s11255-016-1439-0. [67] JIN J, JIN L, LIM SW, et al. Klotho deficiency aggravates tacrolimus-induced renal injury via the phosphatidylinositol 3-kinase-Akt-forkhead box protein O pathway[J]. Am J Nephrol, 2016, 43(5):357-365. DOI: 10.1159/000446447. [68] LIM SW, JIN L, LUO K, et al. Klotho enhances FoxO3-mediated manganese superoxide dismutase expression by negatively regulating PI3K/Akt pathway during tacrolimus-induced oxidative stress[J]. Cell Death Dis, 2017, 8(8): e2972. DOI: 10.1038/cddis.2017.365. [69] LIM SW, SHIN YJ, LUO K, et al. Effect of Klotho on autophagy clearance in tacrolimus-induced renal injury[J]. FASEB J, 2019, 33(2):2694-2706. DOI: 10.1096/fj. 201800751R.
点击查看大图
计量
- 文章访问数: 270
- HTML全文浏览量: 187
- PDF下载量: 19
- 被引次数: 0