Thromb Haemost 2010; 104(06): 1124-1132
DOI: 10.1160/TH10-02-0101
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue

Yosuke Kanno
1   Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women’s Collage of Liberal Arts, Kyoto, Japan
,
Hiroyuki Matsuno
1   Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women’s Collage of Liberal Arts, Kyoto, Japan
,
Eri Kawashita
1   Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women’s Collage of Liberal Arts, Kyoto, Japan
,
Kiyotaka Okada
2   Department of Physiology, Kinki University School of Medicine, Osaka, Japan
,
Hidetaka Suga
3   Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
,
Shigeru Ueshima
2   Department of Physiology, Kinki University School of Medicine, Osaka, Japan
4   Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, Japan
,
Osamu Matsuo
2   Department of Physiology, Kinki University School of Medicine, Osaka, Japan
› Author Affiliations
Further Information

Publication History

Received: 08 February 2010

Accepted after major revision: 28 July 2010

Publication Date:
24 November 2017 (online)

Summary

Urokinase-type plasminogen activator receptor (uPAR) plays a role in cellular responses which include cellular adhesion, differentiation, proliferation and migration. The aim of this study was to clarify the role of uPAR on the development of adipose tissue. To clarify the role of uPAR on adipogenesis, we examined the effect of uPAR overexpression and uPAR deficiency on the adipocyte differentiation. Adipocyte differentiation was induced by incubation of 3T3-L1 cells with differentiation media containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthin. uPAR overexpression by transfection of uPAR expression vector induced adipocyte differentiation. In addition, we examined the difference in adipocyte differentiation of mesenchymal stem cells from wild-type mice and uPAR knockout (uPAR-/-) mice. The uPAR deficiency attenuated differentiation media-induced adipocyte differentiation. Moreover, we found that the inhibition of phosphatidylinositol 3-kinase (PI3K) pathway attenuated uPAR overexpression-induced adipocyte differentiation, and uPAR overexpression induced the activation of Akt. We also found that an increase of the adipose tissue mass in uPAR-/- mice was less than that observed in wild-type mice. The present results suggest that uPAR plays a pivotal role in the development of adipose tissue through PI3K/Akt pathway.

 
  • References

  • 1 Braaten JV, Handt S, Jerome WG. et al. Regulation of fibrinolysis by platelet-released plasminogen activator inhibitor 1: light scattering and ultrastructural examination of lysis of a model platelet-fibrin thrombus. Blood 1993; 81: 1290-1299.
  • 2 Selvarajan S, Lund LR, Takeuchi T. et al. A plasma kallikrein-dependent plasminogen cascade required for adipocyte differentiation. Nat Cell Biol 2001; 3: 267-275.
  • 3 Hoover-Plow J, Yuen L. Plasminogen binding is increased with adipocyte differentiation. Biochem Biophys Res Commun 2001; 284: 389-394.
  • 4 Morange PE, Bastelica D, Bonzi MF. et al. Influence of t-pA and u-PA on adipose tissue development in a murine model of diet-induced obesity. Thromb Haemost 2002; 87: 306-310.
  • 5 Hoover-Plow J, Ellis J, Yuen L. In vivo plasminogen deficiency reduces fat accumulation. Thromb Haemost 2002; 87: 1011-1019.
  • 6 Lijnen H. Deficiency of alpha2-antiplasmin does not affect murine adipose tissue development. J Thromb Haemost 2007; 5: 420-421.
  • 7 Mondino A, Resnati M, Blasi F. Structure and function of the urokinase receptor. Thromb Haemost 1999; 82: 19-22.
  • 8 Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3: 932-943.
  • 9 Kanno Y, Kuroki A, Minamida M. et al. The absence of uPAR attenuates insulin-induced vascular smooth muscle cell migration and proliferation. Thromb Res 2008; 123: 336-341.
  • 10 Sidenius N, Blasi F. The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev 2003; 22: 205-222.
  • 11 Raghunath PN, Tomaszewski JE, Brady ST. et al. Plasminogen activator system in human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 1995; 15: 1432-1443.
  • 12 Salame MY, Samani NJ, Masood I. et al. Expression of the plasminogen activator system in the human vascular wall. Atherosclerosis 2000; 152: 19-28.
  • 13 Bujo H, Saito Y. Modulation of smooth muscle cell migration by members of the low-density lipoprotein receptor family. Arterioscler Thromb Vasc Biol 2006; 26: 1246-1252.
  • 14 Bernstein AM, Twining SS, Warejcka DJ. et al. Urokinase receptor cleavage: a crucial step in fibroblast-to-myofibroblast differentiation. Mol Biol Cell 2007; 18: 2716-2727.
  • 15 D’Alessio S, Fibbi G, Cinelli M. et al. Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis Rheum 2004; 50: 3275-3285.
  • 16 Margheri F, Manetti M, Serratì S. et al. Domain 1 of the urokinase-type plasminogen activator receptor is required for its morphologic and functional, beta2 integrin-mediated connection with actin cytoskeleton in human microvascular endothelial cells: failure of association in systemic sclerosis endothelial cells. Arthritis Rheum 2006; 54: 3926-3938.
  • 17 Zhang G, Kim H, Cai X. et al.. Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy. J Am Soc Nephrol 2003; 14: 1254-1271.
  • 18 Kanno Y, Kaneiwa A, Minamida M. et al. The absence of uPAR is associated with the progression of dermal fibrosis. J Invest Dermatol 2008; 128: 2792-2797.
  • 19 Peng XD, Xu PZ, Chen ML. et al. Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev 2003; 17: 1352-1365.
  • 20 Baudry A, Yang ZZ, Hemmings BA. PKBalpha is required for adipose differentiation of mouse embryonic fibroblasts. J Cell Sci 2006; 119: 889-897.
  • 21 Xu J, Liao K. Protein kinase B/AKT 1 plays a pivotal role in insulin-like growth factor-1 receptor signaling induced 3T3-L1 adipocyte differentiation. J Biol Chem 2004; 279: 35914-35922.
  • 22 Kohn AD, Summers SA, Birnbaum MJ. et al. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem 1996; 271: 31372-31378.
  • 23 Yun SJ, Kim EK, Tucker DF. et al. Isoform-specific regulation of adipocyte differentiation by Akt/protein kinase Balpha. Biochem Biophys Res Commun 2008; 371: 138-143.
  • 24 Gondi CS, Kandhukuri N, Dinh DH. et al. Down-regulation of uPAR and uPA activates caspase-mediated apoptosis and inhibits the PI3K/AKT pathway. Int J Oncol 2007; 31: 19-27.
  • 25 Dewerchin M, Nuffelen AV, Wallays G. et al. Generation and characterization of urokinase receptor-deficient mice. J Clin Invest 1996; 97: 870-878.
  • 26 Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 1999; 96: 10711-10716.
  • 27 Kanno Y, Into T, Lowenstein CJ. et al. Nitric oxide regulates vascular calcification by interfering with TGF- signalling. Cardiovasc Res 2008; 77: 221-230.
  • 28 Lehrke M, Lazar MA. The many faces of PPARgamma. Cell 2005; 123: 993-999.
  • 29 Davies SP, Reddy H, Caivano M. et al. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000; 351: 95-105.
  • 30 Novakofski J. Adipogenesis: usefulness of in vitro and in vivo experimental models. J Anim Sci 82: 905-915.
  • 31 Sakamoto K, Goodyear LJ. Invited review: intracellular signaling in contracting skeletal muscle. J Appl Physiol 2002; 93: 369-383.
  • 32 Binder BR, Mihaly J, Prager GW. uPAR-uPA-PAI-1 interactions and signaling: a vascular biologist’s view. Thromb Haemost 2007; 97: 336-342.
  • 33 Madsen CD, Ferraris GM, Andolfo A, Cunningham O, Sidenius N. 2007. uPAR-induced cell adhesion and migration: vitronectin provides the key. J Cell Biol 2007; 177: 927-939.
  • 34 Crandall DL, Busler DE, McHendry-Rinde B. et al. Autocrine regulation of human preadipocyte migration by plasminogen activator inhibitor-1. J Clin Endocrinol Metab 2000; 85: 2609-2614.
  • 35 Wei C, Möller CC, Altintas MM. et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 2008; 14: 55-63.
  • 36 Aguirre-Ghiso JA, Liu D, Mignatti A. et al. Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell 2001; 12: 863-879.
  • 37 Farnier C, Krief S, Blache M. et al. Adipocyte functions are modulated by cell size change: potential involvement of an integrin/ERK signalling pathway. Int J Obes Relat Metab Disord 2003; 27: 1178-1186.
  • 38 Ma Z, Thomas KS, Webb DJ. et al. Regulation of Rac1 activation by the low density lipoprotein receptor-related protein. J Cell Biol 2002; 159: 1061-1070.
  • 39 Terrand J, Bruban V, Zhou L. et al. LRP1 controls intracellular cholesterol storage and fatty acid synthesis through modulation of Wnt signaling. J Biol Chem 2009; 284: 381-388.
  • 40 Sakaue H, Ogawa W, Matsumoto M. et al. Posttranscriptional control of adipocyte differentiation through activation of phosphoinositide 3-kinase. J Biol Chem 1998; 273: 28945-28952.
  • 41 Fu M, Zhu X, Wang Q. et al. Platelet-derived growth factor promotes the expression of peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells by a phosphatidylinositol 3-kinase/Akt signaling pathway. Circ Res 2001; 89: 1058-1064.
  • 42 Hofmann SM, Zhou L, Perez-Tilve D. et al. Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. J Clin Invest 2007; 117: 3271-3282.