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Journal of Nephrology

Erschienen in:

01.02.2019 | Original Article

Activation of the mTORC1 pathway by inflammation contributes to vascular calcification in patients with end-stage renal disease

verfasst von: Jing Liu, Wei Zhu, Chun Ming Jiang, Yuan Feng, Yang Yang Xia, Qing Yan Zhang, Miao Zhang

Erschienen in: Journal of Nephrology | Ausgabe 1/2019

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Abstract

Background

Chronic inflammation plays an important role in the progression of vascular calcification (VC). This study was designed to explore the effects and underlying mechanisms of inflammation on VC in the radial arteries of patients with end-stage renal disease (ESRD) with arteriovenostomy.

Methods

Forty-eight ESRD patients were divided into control (n = 25) and inflammation groups (n = 23) according to plasma C-reactive protein (CRP) level. Surgically removed tissues from the radial arteries of patients receiving arteriovenostomy were used in this study. Alizarin Red S staining was used to examine calcium deposition. The expression of inflammation markers, bone structure-associated proteins and mammalian target of rapamycin complex1 (mTORC1) pathway-related proteins was assessed by immunohistochemical staining.

Results

The expression of tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1) was increased in the radial arteries of the inflammation group. Additionally, Alizarin Red S staining revealed a marked increase in calcium deposition in the inflammation group compared to controls. Further analysis by immunohistochemical staining demonstrated that the deposition was correlated with the increased expression of bone-associated proteins such as bone morphogenetic proteins-2 (BMP-2) and osteocalcin and collagen I, which suggested that inflammation induces osteogenic differentiation in vascular tissues and that osteogenic cells are the main cellular components involved in VC. Interestingly, there was a parallel increase in the expression of phosphorylated mTOR (p-mTOR) and pribosomal protein S6 kinase 1 (p-S6K1) in the inflammation group. Furthermore, mTORC1 pathway-related proteins were significantly associated with the enhanced expression of bone formation biomarkers.

Conclusions

Inflammation contributed to VC in the radial arteries of ESRD patients via the induction of osteogenic differentiation in vessel walls, which could be regulated by the activation of the mTORC1 pathway.

Foley RN, Murray AM, Li S, Herzog CA, McBean AM, Eggers PW, Collins AJ (2005) Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 16(2):489–495. https://doi.org/10.1681/ASN.2004030203 CrossRef

Stenvinkel P, Carrero JJ, Axelsson J, Lindholm B, Heimbürger O, Massy Z (2008) Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces t into the uremic puzzle? Clin J Am Soc Nephrol 3(2):505–521. https://doi.org/10.2215/CJN.03670807 CrossRefPubMedPubMedCentral

Kaysen GA (2001) The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol 12(7):1549–1557PubMed

Chen NC, Hsu CY, Chen CL (2017) The strategy to prevent and regress the vascular calcification in dialysis patients. Biomed Res Int 2017:9035193. https://doi.org/10.1155/2017/9035193

Yamada S, Tokumoto M, Tatsumoto N, Taniguchi M, Noguchi H, Nakano T, Masutani K, Ooboshi H, Tsuruya K, Kitazono T (2014) Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia. Am J Physiol Renal Physiol 306(12):1418–1428. https://doi.org/10.1152/ajprenal.00633.2013 CrossRef

Yoshihara F (2016) Systemic inflammation is a key factor for mortality risk stratification in chronic kidney disease patients with coronary artery calcification. Circ J 80(7):1537–1538. https://doi.org/10.1253/circj.CJ-16-0506 CrossRefPubMed

Evrard S, Delanaye P, Kamel S, Cristol JP, Cavalier E (2015) Vascular calcification: from pathophysiology to biomarkers. Clin Chim Acta 438:401–414. https://doi.org/10.1016/j.cca.2014.08.034 CrossRefPubMed

Lau WL, Ix JH (2013) Clinical detection, risk factors, and cardiovascular consequences of medial arterial calci cation: a pattern of vascular injury associated with aberrant mineral metabolism. Semin Nephrol 33(2):93–105. https://doi.org/10.1016/j.semnephrol.2012.12.011 CrossRefPubMed

Steitz SA, Speer MY, Curinga G, Yang HY, Haynes P, Aebersold R, Schinke T, Karsenty G, Giachelli CM (2001) Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 89(12):1147–1154CrossRefPubMed

10.

Neven E, Dauwe S, De Broe ME, D’Haese PC, Persy V (2007) Endochondral bone formation is involved in media calcification in rats and in men. Kidney Int 72(5):574–581. https://doi.org/10.1038/sj.ki.5002353 CrossRefPubMed

11.

Towler DA (2013) Molecular and cellular aspects of calcific aortic valve disease. Circ Res 113(2):198–208. https://doi.org/10.1161/CIRCRESAHA.CrossRefPubMedPubMedCentral

12.

Barreto FC, Barreto DV, Moyses RM, Neves CL, Jorgetti V, Draibe SA, Canziani ME, Carvalho AB (2006) Osteoporosis in hemodial-ysis patients revisited by bone histomorphometry: a new insight into an old problem. Kidney Int 69(10):1852–1857CrossRefPubMed

13.

Cai T, Sun D, Duan Y, Wen P, Dai C, Yang J, He W (2016) WNT/β-catenin signaling promotes VSMCs to osteogenic transdifferentiation and calcification through directly modulating Runx2 gene expression. Exp Cell Res 345(2):206–217. https://doi.org/10.1016/j.yexcr.2016.06.007 CrossRefPubMed

14.

Khosla S (2011) The bone and beyond: a shift in calcium. Nat Med 17(4):430–431. https://doi.org/10.1038/nm0411-430 CrossRefPubMed

15.

Hruska KA, Mathew S, Lund RJ, Memon I, Saab G (2009) The pathogenesis of vascular calcification in the chronic kidney disease mineral bone disorder: the links between bone and the vasculature. Semin Nephrol 29(2):156–165. https://doi.org/10.1016/j.semnephrol CrossRefPubMedPubMedCentral

16.

Alesutan I, Voelkl J, Feger M, Kratschmar DV, Castor T, Mia S, Sacherer M, Viereck R, Borst O, Leibrock C, Gawaz M, Kuro-O M, Pilz S, Tomaschitz A, Odermatt A, Pieske B, Wagner CA, Lang F (2017) Involvement of vascular aldosterone synthase in phosphate-induced osteogenic transformation of vascular smooth muscle cells. Sci Rep 7(1):2059. https://doi.org/10.1038/s41598-017-01882-2 CrossRefPubMedPubMedCentral

17.

Jewell JL, Guan KL (2013) Nutrient signaling to mTOR and cell growth. Trends Biochem Sci 38(5):233–242. https://doi.org/10.1016/j.tibs.2013.01.004 CrossRefPubMedPubMedCentral

18.

Zhao Y, Zhao MM, Cai Y, Zheng MF, Sun WL, Zhang SY, Kong W, Gu J, Wang X, Xu MJ (2015) Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation. Kidney Int 88(4):711–721. https://doi.org/10.1038/ki.2015.160 CrossRefPubMed

19.

Vervloet MG, Adema AY, Larsson TE, Massy ZA (2014) The role of klotho on vascular calcification and endothelial function in chronic kidney disease. Semin Nephrol 34(6):578–585. https://doi.org/10.1016/j.semnephrol.2014.09.003 CrossRefPubMed

20.

Yeh LC, Ma X, Ford JJ, Adamo ML, Lee JC (2013) Rapamycin inhibits BMP-7-induced osteogenic and lipogenic marker expressions in fetal rat calvarial cells. J Cell Biochem 114(8):1760–1771. https://doi.org/10.1002/jcb.24519 CrossRefPubMed

21.

Ma KL, Liu J, Wang CX, Ni J, Zhang Y, Wu Y, Lv LL, Ruan XZ, Liu BC (2013) Activation of mTOR modulates SREBP-2 to induce foam cell formation through increased retinoblastoma protein phosphorylation. Cardiovasc Res 100(3):450–460. https://doi.org/10.1093/cvr/cvt203 CrossRefPubMed

22.

Liu J, Ma KL, Zhang Y, Wu Y, Hu ZB, Lv LL, Tang RN, Liu H, Ruan XZ, Liu BC (2015) Activation of mTORC1 disrupted LDL receptor pathway: a potential new mechanism for the progression of non-alcoholic fatty liver disease. Int J Biochem Cell Biol 61:8–19. https://doi.org/10.1016/j.biocel.2015.01.011 CrossRefPubMed

23.

Jung HH, Kim SW, Han H (2006) Inflammation, mineral metabolism and progressive coronary artery calcification in patients on haemodialysis. Nephrol Dial Transplant 21(7):1915–1920. https://doi.org/10.1093/ndt/gfl118 CrossRefPubMed

24.

Liu J, Ma KL, Gao M, Wang CX, Ni J, Zhang Y, Zhang XL, Liu H, Wang YL, Liu BC (2012) Inflammation disrupts the LDL receptor pathway and accelerates the progression of vascular calcification in ESRD patients. PLoS One 7(10):47217. https://doi.org/10.1371/journal.pone.0047217 CrossRef

25.

Din ASharafE, Salem UA, Abdulazim MM DO (2016) Vascular calcification: when should we interfere in chronic kidney disease patients and how? World J Nephrol 5(5):398–417. https://doi.org/10.5527/wjn.v5.i5.398 CrossRef

26.

Hwang IC, Park HE, Kim HL, Kim HM, Park JB, Yoon YE, Lee SP, Kim HK, Cho GY, Sohn DW, Kim YJ (2016) Systemic in ammation is associated with coronary artery calcifica-tion and all-cause mortality in chronic kidney disease. Circ J 80(7):1644–1652. https://doi.org/10.1253/circj.CJ-15-1224 CrossRefPubMed

27.

Martínez-Moreno JM1, Muñoz-Castañeda JR, Herencia C, Oca AM, Estepa JC, Canalejo R, Rodríguez-Ortiz ME, Perez-Martinez P, Aguilera-Tejero E, Canalejo A, Rodríguez M, Almadén Y (2012) In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/β-catenin activation. Am J Physiol Renal Physiol 303(8):1136–1144. https://doi.org/10.1152/ajprenal.00684.2011 CrossRef

28.

Viaene L, Behets GJ, Heye S, Claes K, Monbaliu D, Pirenne J, D’Haese PC, Evenepoel P (2016) Inflammation and the bone-vascular axis in end-stage renal disease. Osteoporos Int 27(2):489–497. https://doi.org/10.1007/s00198-015-3233-8.CrossRefPubMed

29.

Cheng L, Zhang L, Yang J, Hao L (2017) Activation of peroxisome proliferatoractivated receptor γ inhibits vascular calcification by upregulating Klotho. Exp Ther Med 13(2):467–474. https://doi.org/10.3892/etm.2016.3996 CrossRefPubMed

30.

Montezano AC, Touyz RM (2014) Mammalian target of rapamycin: a novel pathway in vascular calcification. Can J Cardiol 30(5):482–484. https://doi.org/10.1016/j.cjca.2014.03.001 CrossRefPubMed

31.

Hu Y, Lou J, Mao YY, Lai TW, Liu LY, Zhu C, Zhang C, Liu J, Li YY, Zhang F, Li W, Ying SM, Chen ZH, Shen HH (2016) Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury. Autophagy 12(12):2286–2299. https://doi.org/10.1080/15548627.2016.1230584 docCrossRefPubMedPubMedCentral

32.

Xiao Z, Peng J, Gan N, Arafat A, Yin F (2016) Interleukin-1β plays a pivotal role via the PI3K/Akt/mTOR signaling pathway in the chronicity of mesial temporal lobe epilepsy. Neuroimmunomodulation 23(5–6):332–344. https://doi.org/10.1159/000460254 CrossRef

33.

Xian L, Wu X, Pang L, Lou M, Rosen CJ, Qiu T, Crane J, Frassica F, Zhang L, Rodriguez JP, Jia X, Yakar S, Xuan S, Efstratiadis A, Wan M, Cao X (2012) Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med 18(7):1095–1101. https://doi.org/10.1038/nm.2793 CrossRefPubMedPubMedCentral

34.

Zhan JK, Wang YJ, Wang Y, Wang S, Tan P, Huang W, Liu YS (2014) The mammalian target of rapamycin signalling pathway is involved in osteoblastic differentiation of vascular smooth muscle cells. Can J Cardiol 30(5):568–575. https://doi.org/10.1016/j.cjca.2013.11.005 CrossRefPubMed

Titel: Activation of the mTORC1 pathway by inflammation contributes to vascular calcification in patients with end-stage renal disease
verfasst von: Jing Liu
Wei Zhu
Chun Ming Jiang
Yuan Feng
Yang Yang Xia
Qing Yan Zhang
Miao Zhang
Publikationsdatum: 01.02.2019
Verlag: Springer International Publishing
Erschienen in: Journal of Nephrology / Ausgabe 1/2019
Print ISSN: 1121-8428
Elektronische ISSN: 1724-6059
DOI: https://doi.org/10.1007/s40620-018-0486-2

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Abstract

Background

Methods

Results

Conclusions

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