Takamune Takahashi, M.D., Ph.D.

Associate Professor

takamune.takahashi@vanderbilt.edu
Faculty Appointments
Associate Professor of Medicine Associate Professor of Cancer Biology
Education
Ph.D., Medical Science (Molecular Pathology), Jikei University, TokyoM.D., Medicine, Jikei University, Tokyo
Office Address
S-3223 MCN
1161 21st Avenue South
Nashville, TN 37232-2372
Research Description
Angiogenesis, formation of new blood vessels, is a pivotal process in organogenesis and tissue regeneration, requiring ordered endothelial cell proliferation, migration, and homotypic and heterotypic intercellular adhesion. However, when angiogenesis is induced (and unregulated) in pathological conditions, it greatly contributes to the progression of disease, including cancer, diabetes, ischemic, and inflammatory disorders. Thus, definition of the intrinsic molecular controls that regulate angiogenic vessel growth promises novel therapeutic approaches for angiogenesis-associated diseases.
In the recent decades, investigators have identified various endothelial cell surface receptors and their activating ligands that promote and coordinate angiogenic vessel formation. However, much less is known about the endothelial receptors that transduce "anti-angiogenic (or angiostatic)" signals, though they could be used for angiogenesis inhibition. CD148 (DEP-1/PTPeta) is a transmembrane tyrosine phosphatase which is abundantly expressed in vascular endothelial cells of various tissues. We have shown that CD148 suppresses endothelial growth factor signals and strongly inhibits endothelial cell growth in culture and in vivo. Further, we have recently found that thrombospondin-1 (TSP-1) serves as an agonistic ligand for CD148. We are currently determining: 1. the role of CD148 in postnatal angiogenesis (physiological and pathological); 2. the role of TSP-1 and CD148 interaction in angiogenesis. These efforts should explore new pathways of angiogenesis inhibition and provide a novel strategy for anti-angiogenesis therapy.

Another project in the lab examines the mechanisms of diabetic renal microvascular injury. We found that loss of eNOS or SOD enzyme largely exacerbates diabetic glomerular microvascular injury in mice. The lab examines the detailed mechanisms of this using conditional as well as global knockout mouse.

Last, as a primary lab of Vanderbilt O¿¿¿Brien Mouse Kidney Physiology and Disease Center (MKPDC), the lab and VUIIS scientists are developing non-invasive kidney imaging techniques that enable structural, functional, and molecular assessments of mouse kidney disease in living animals.

Research Keywords
Molecular Basis of Angiogenesis, Renal Biology and Pathology, Endothelial Pathology
Publications
Wang F, Jiang R, Takahashi K, Gore J, Harris RC, Takahashi T, Quarles CC. Longitudinal assessment of mouse renal injury using high-resolution anatomic and magnetization transfer MR imaging. Magn Reson Imaging [print-electronic]. 2014 Nov; 32(9): 1125-32. PMID: 25093632, PMCID: PMC4171209, PII: S0730-725X(14)00215-X, DOI: 10.1016/j.mri.2014.07.012, ISSN: 1873-5894.

Wang F, Jiang RT, Tantawy MN, Borza DB, Takahashi K, Gore JC, Harris RC, Takahashi T, Quarles CC. Repeatability and sensitivity of high resolution blood volume mapping in mouse kidney disease. J Magn Reson Imaging [print-electronic]. 2014 Apr; 39(4): 866-71. PMID: 24006202, PMCID: PMC3858530, DOI: 10.1002/jmri.24242, ISSN: 1522-2586.

Fujita H, Morii T, Fujishima H, Sato T, Shimizu T, Hosoba M, Tsukiyama K, Narita T, Takahashi T, Drucker DJ, Seino Y, Yamada Y. The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. Kidney Int [print-electronic]. 2014 Mar; 85(3): 579-89. PMID: 24152968, PII: ki2013427, DOI: 10.1038/ki.2013.427, ISSN: 1523-1755.

Takahashi K, Matafonov A, Sumarriva K, Ito H, Lauhan C, Zemel D, Tsuboi N, Chen J, Reynolds A, Takahashi T. CD148 tyrosine phosphatase promotes cadherin cell adhesion. PLoS ONE. 2014; 9(11): e112753. PMID: 25386896, PMCID: PMC4227875, PII: PONE-D-14-33624, DOI: 10.1371/journal.pone.0112753, ISSN: 1932-6203.

Takahashi T, Harris RC. Role of endothelial nitric oxide synthase in diabetic nephropathy: lessons from diabetic eNOS knockout mice. J Diabetes Res [print-electronic]. 2014; 2014: 590541. PMID: 25371905, PMCID: PMC4211249, DOI: 10.1155/2014/590541, ISSN: 2314-6753.

Dai C, Brissova M, Reinert RB, Nyman L, Liu EH, Thompson C, Shostak A, Shiota M, Takahashi T, Powers AC. Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis. Diabetes [print-electronic]. 2013 Dec; 62(12): 4144-53. PMID: 23630302, PMCID: PMC3837044, PII: db12-1657, DOI: 10.2337/db12-1657, ISSN: 1939-327X.

Fujita H, Fujishima H, Takahashi K, Sato T, Shimizu T, Morii T, Shimizu T, Shirasawa T, Qi Z, Breyer MD, Harris RC, Yamada Y, Takahashi T. SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2(Akita) diabetic mice. Metab. Clin. Exp [print-electronic]. 2012 Dec; 61(12): 1714-24. PMID: 22632894, PMCID: PMC4360989, PII: S0026-0495(12)00191-6, DOI: 10.1016/j.metabol.2012.05.005, ISSN: 1532-8600.

Jiang R, Wang S, Takahashi K, Fujita H, Fruci CR, Breyer MD, Harris RC, Takahashi T. Generation of a conditional allele for the mouse endothelial nitric oxide synthase gene. Genesis [print-electronic]. 2012 Sep; 50(9): 685-92. PMID: 22467476, PMCID: PMC3399989, DOI: 10.1002/dvg.22026, ISSN: 1526-968X.

Zhang MZ, Wang S, Yang S, Yang H, Fan X, Takahashi T, Harris RC. Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS-/- db/db mice. Am. J. Physiol. Renal Physiol [print-electronic]. 2012 Feb 2/15/2012; 302(4): F433-8. PMID: 22114203, PMCID: PMC3289417, PII: ajprenal.00292.2011, DOI: 10.1152/ajprenal.00292.2011, ISSN: 1522-1466.

Takahashi K, Mernaugh RL, Friedman DB, Weller R, Tsuboi N, Yamashita H, Quaranta V, Takahashi T. Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2012 Feb 2/7/2012; 109(6): 1985-90. PMID: 22308318, PMCID: PMC3277540, PII: 1106171109, DOI: 10.1073/pnas.1106171109, ISSN: 1091-6490.

Tantawy MN, Jiang R, Wang F, Takahashi K, Peterson TE, Zemel D, Hao CM, Fujita H, Harris RC, Quarles CC, Takahashi T. Assessment of renal function in mice with unilateral ureteral obstruction using 99mTc-MAG3 dynamic scintigraphy. BMC Nephrol. 2012; 13: 168. PMID: 23228112, PMCID: PMC3542003, PII: 1471-2369-13-168, DOI: 10.1186/1471-2369-13-168, ISSN: 1471-2369.

Beckham JT, Wilmink GJ, Opalenik SR, Mackanos MA, Abraham AA, Takahashi K, Contag CH, Takahashi T, Jansen ED. Microarray analysis of cellular thermotolerance. Lasers Surg Med. 2010 Dec; 42(10): 752-65. PMID: 21246580, DOI: 10.1002/lsm.20983, ISSN: 1096-9101.

Tarcic G, Boguslavsky SK, Wakim J, Kiuchi T, Liu A, Reinitz F, Nathanson D, Takahashi T, Mischel PS, Ng T, Yarden Y. An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase controlling EGFR endocytosis. Curr. Biol. 2009 Nov 11/17/2009; 19(21): 1788-98. PMID: 19836242, PMCID: PMC2783429, PII: S0960-9822(09)01761-8, DOI: 10.1016/j.cub.2009.09.048, ISSN: 1879-0445.

Sacco F, Tinti M, Palma A, Ferrari E, Nardozza AP, Hooft van Huijsduijnen R, Takahashi T, Castagnoli L, Cesareni G. Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases. J. Biol. Chem [print-electronic]. 2009 Aug 8/14/2009; 284(33): 22048-58. PMID: 19494114, PMCID: PMC2755929, PII: M109.002758, DOI: 10.1074/jbc.M109.002758, ISSN: 0021-9258.

Fujita H, Fujishima H, Chida S, Takahashi K, Qi Z, Kanetsuna Y, Breyer MD, Harris RC, Yamada Y, Takahashi T. Reduction of renal superoxide dismutase in progressive diabetic nephropathy. J. Am. Soc. Nephrol [print-electronic]. 2009 Jun; 20(6): 1303-13. PMID: 19470681, PMCID: PMC2689908, PII: ASN.2008080844, DOI: 10.1681/ASN.2008080844, ISSN: 1533-3450.

Beckham JT, Wilmink GJ, Mackanos MA, Takahashi K, Contag CH, Takahashi T, Jansen ED. Role of HSP70 in cellular thermotolerance. Lasers Surg Med. 2008 Dec; 40(10): 704-15. PMID: 19065555, DOI: 10.1002/lsm.20713, ISSN: 1096-9101.

Yamamoto I, Horita S, Takahashi T, Kobayashi A, Toki D, Tanabe K, Hattori M, Teraoka S, Aita K, Nagata M, Yamaguchi Y. Caveolin-1 expression is a distinct feature of chronic rejection-induced transplant capillaropathy. Am. J. Transplant. 2008 Dec; 8(12): 2627-35. PMID: 19032226, PII: AJT2421, DOI: 10.1111/j.1600-6143.2008.02421.x, ISSN: 1600-6143.

Tsuboi N, Utsunomiya T, Roberts RL, Ito H, Takahashi K, Noda M, Takahashi T. The tyrosine phosphatase CD148 interacts with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem. J. 2008 Jul 7/1/2008; 413(1): 193-200. PMID: 18348712, PII: BJ20071317, DOI: 10.1042/BJ20071317, ISSN: 1470-8728.

Fang WB, Ireton RC, Zhuang G, Takahashi T, Reynolds A, Chen J. Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. J. Cell. Sci [print-electronic]. 2008 Feb 2/1/2008; 121(Pt 3): 358-68. PMID: 18198190, PII: jcs.017145, DOI: 10.1242/jcs.017145, ISSN: 0021-9533.

Ito H, Fujita H, Takahashi T. Diagnostic biomarkers of diabetic nephropathy. Expert Opin Med Diagn. 2008 Feb; 2(2): 161-9. PMID: 23485136, DOI: 10.1517/17530059.2.2.161, ISSN: 1753-0059.

Breyer MD, Tchekneva E, Qi Z, Takahashi T, Fogo AB, Harris RC. Examining diabetic nephropathy through the lens of mouse genetics. Curr. Diab. Rep. 2007 Dec; 7(6): 459-66. PMID: 18255011, ISSN: 1534-4827.

Faley SL, Takahashi K, Crooke CE, Beckham JT, Tomemori T, Shappell SB, Jansen ED, Takahashi T. Bioluminescence imaging of vascular endothelial growth factor promoter activity in murine mammary tumorigenesis. Mol Imaging. 2007 Sep; 6(5): 331-9. PMID: 18092518, ISSN: 1535-3508.

Yamamoto I, Horita S, Takahashi T, Tanabe K, Fuchinoue S, Teraoka S, Hattori M, Yamaguchi Y. Glomerular expression of plasmalemmal vesicle-associated protein-1 in patients with transplant glomerulopathy. Am. J. Transplant. 2007 Aug; 7(8): 1954-60. PMID: 17617859, PII: AJT1876, DOI: 10.1111/j.1600-6143.2007.01876.x, ISSN: 1600-6135.

Kanetsuna Y, Takahashi K, Nagata M, Gannon MA, Breyer MD, Harris RC, Takahashi T. Deficiency of endothelial nitric-oxide synthase confers susceptibility to diabetic nephropathy in nephropathy-resistant inbred mice. Am. J. Pathol. 2007 May; 170(5): 1473-84. PMID: 17456755, PMCID: PMC1854944, PII: S0002-9440(10)61362-4, DOI: 10.2353/ajpath.2007.060481, ISSN: 0002-9440.

Breyer MD, Tchekneva E, Qi Z, Takahashi T, Fogo AB, Zhao HJ, Harris RC. Genetics of diabetic nephropathy: lessons from mice. Semin. Nephrol. 2007 Mar; 27(2): 237-47. PMID: 17418691, PII: S0270-9295(07)00002-2, DOI: 10.1016/j.semnephrol.2007.01.001, ISSN: 0270-9295.

Kanetsuna Y, Hirano K, Nagata M, Gannon MA, Takahashi K, Harris RC, Breyer MD, Takahashi T. Characterization of diabetic nephropathy in a transgenic model of hypoinsulinemic diabetes. Am. J. Physiol. Renal Physiol [print-electronic]. 2006 Dec; 291(6): F1315-22. PMID: 16705146, PII: 00379.2005, DOI: 10.1152/ajprenal.00379.2005, ISSN: 1931-857X.

Takahashi T, Morrow JD, Wang H, Dey SK. Cyclooxygenase-2-derived prostaglandin E(2) directs oocyte maturation by differentially influencing multiple signaling pathways. J. Biol. Chem [print-electronic]. 2006 Dec 12/1/2006; 281(48): 37117-29. PMID: 17023426, PII: M608202200, DOI: 10.1074/jbc.M608202200, ISSN: 0021-9258.

Zhao HJ, Wang S, Cheng H, Zhang MZ, Takahashi T, Fogo AB, Breyer MD, Harris RC. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J. Am. Soc. Nephrol [print-electronic]. 2006 Oct; 17(10): 2664-9. PMID: 16971655, PMCID: PMC4618687, PII: ASN.2006070798, DOI: 10.1681/ASN.2006070798, ISSN: 1046-6673.

Takahashi T, Takahashi K, Mernaugh RL, Tsuboi N, Liu H, Daniel TO. A monoclonal antibody against CD148, a receptor-like tyrosine phosphatase, inhibits endothelial-cell growth and angiogenesis. Blood [print-electronic]. 2006 Aug 8/15/2006; 108(4): 1234-42. PMID: 16597593, PMCID: PMC1895872, PII: 2005-10-4296, DOI: 10.1182/blood-2005-10-4296, ISSN: 0006-4971.

Wang H, Xie H, Guo Y, Zhang H, Takahashi T, Kingsley PJ, Marnett LJ, Das SK, Cravatt BF, Dey SK. Fatty acid amide hydrolase deficiency limits early pregnancy events. J. Clin. Invest. 2006 Aug; 116(8): 2122-31. PMID: 16886060, PMCID: PMC1523389, DOI: 10.1172/JCI28621, ISSN: 0021-9738.

Chen J, Boyle S, Zhao M, Su W, Takahashi K, Davis L, Decaestecker M, Takahashi T, Breyer MD, Hao CM. Differential expression of the intermediate filament protein nestin during renal development and its localization in adult podocytes. J. Am. Soc. Nephrol [print-electronic]. 2006 May; 17(5): 1283-91. PMID: 16571784, PII: ASN.2005101032, DOI: 10.1681/ASN.2005101032, ISSN: 1046-6673.

Anumanthan G, Halder SK, Osada H, Takahashi T, Massion PP, Carbone DP, Datta PK. Restoration of TGF-beta signalling reduces tumorigenicity in human lung cancer cells. Br. J. Cancer. 2005 Nov 11/14/2005; 93(10): 1157-67. PMID: 16251876, PMCID: PMC2361493, PII: 6602831, DOI: 10.1038/sj.bjc.6602831, ISSN: 0007-0920.

Parker M, Roberts R, Enriquez M, Zhao X, Takahashi T, Pat Cerretti D, Daniel T, Chen J. Reverse endocytosis of transmembrane ephrin-B ligands via a clathrin-mediated pathway. Biochem. Biophys. Res. Commun. 2004 Oct 10/8/2004; 323(1): 17-23. PMID: 15351694, PII: S0006-291X(04)01590-6, DOI: 10.1016/j.bbrc.2004.07.209, ISSN: 0006-291X.

Xu Y, Kashiwakura I, Takahashi TA. High sensitivity of megakaryocytic progenitor cells contained in placental/umbilical cord blood to the stresses during cryopreservation. Bone Marrow Transplant. 2004 Sep; 34(6): 537-43. PMID: 15273713, PII: 1704632, DOI: 10.1038/sj.bmt.1704632, ISSN: 0268-3369.

Beckham JT, Mackanos MA, Crooke C, Takahashi T, O'Connell-Rodwell C, Contag CH, Jansen ED. Assessment of cellular response to thermal laser injury through bioluminescence imaging of heat shock protein 70. Photochem. Photobiol. 2004 Jan; 79(1): 76-85. PMID: 14974719, ISSN: 0031-8655.

Takahashi T, Takahashi K, St John PL, Fleming PA, Tomemori T, Watanabe T, Abrahamson DR, Drake CJ, Shirasawa T, Daniel TO. A mutant receptor tyrosine phosphatase, CD148, causes defects in vascular development. Mol. Cell. Biol. 2003 Mar; 23(5): 1817-31. PMID: 12588999, PMCID: PMC151692, ISSN: 0270-7306.

Grazia Lampugnani M, Zanetti A, Corada M, Takahashi T, Balconi G, Breviario F, Orsenigo F, Cattelino A, Kemler R, Daniel TO, Dejana E.. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148. J Cell Biol. 2003; 26((161)): 793-804.

Usui J, Kurihara H, Shu Y, Tomari S, Kanemoto K, Koyama A, Sakai T, Takahashi T, Nagata M.. Localization of intercellular adherens junction protein p120 catenin during podocyte differentiation. Anat Embryol (Berl). 2003; 206((3)): 175-84.

Takahashi T, Takahashi K, Gerety S, Wang H, Anderson DJ, Daniel TO. Temporally compartmentalized expression of ephrin-B2 during renal glomerular development. J. Am. Soc. Nephrol. 2001 Dec; 12(12): 2673-82. PMID: 11729236, ISSN: 1046-6673.

Dikov MM, Oyama T, Cheng P, Takahashi T, Takahashi K, Sepetavec T, Edwards B, Adachi Y, Nadaf S, Daniel T, Gabrilovich DI, Carbone DP. Vascular endothelial growth factor effects on nuclear factor-kappaB activation in hematopoietic progenitor cells. Cancer Res. 2001 Mar 3/1/2001; 61(5): 2015-21. PMID: 11280761, ISSN: 0008-5472.

Daniel TO, Stein E, Huynh-Do U, Takahashi T. 4 signaling between endothelial progenitor cells. J. Histochem. Cytochem. 1999 Dec; 47(12): 1643C-1644. PMID: 10567451, ISSN: 1551-5044.

Takahashi T, Takahashi K, Mernaugh R, Drozdoff V, Sipe C, Schoecklmann H, Robert B, Abrahamson DR, Daniel TO. Endothelial localization of receptor tyrosine phosphatase, ECRTP/DEP-1, in developing and mature renal vasculature. J. Am. Soc. Nephrol. 1999 Oct; 10(10): 2135-45. PMID: 10505690, ISSN: 1046-6673.

Takahashi T., Takahashi K. and Daniel TO.. High Efficiency & Low Toxicity Adenovirus- assisted Endothelial Transfection. Methods in Molecular Medicine, Vascular Disease: Molecular Biology and Gene Therapy Protocols. 1999; 304-14.

Takahashi T, Huynh-Do U, Daniel TO. Renal microvascular assembly and repair: power and promise of molecular definition. Kidney Int. 1998 Apr; 53(4): 826-35. PMID: 9551388, DOI: 10.1111/j.1523-1755.1998.00822.x, ISSN: 0085-2538.

Takahashi T, Shirasawa T, Miyake K, Yahagi Y, Matsumura O, Abe A, Natori Y, Yamabe H, Utsunomiya Y, Maruyama N, Mitarai T, Sakai O.. Jak3 expression in glomerular epithelia of IgA nephropathy (IgA-N) patients. Clin Exp Immunol. 1996; 104((3)): 517-24.

Park SY, Saijo K, Takahashi T, Osawa M, Arase H, Hirayama N, Miyake K, Nakauchi H, Shirasawa T, Saito T.. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity. 1995; 3((6)): 771-82.

Takahashi T, Shirasawa T, Miyake K, Yahagi Y, Maruyama N, Kasahara N, Kawamura T, Matsumura O, Mitarai T, Sakai O.. Protein tyrosine kinases expressed in glomeruli and cultured glomerular cells: Flt-1 and VEGF expression in renal mesangial cells. Biochem Biophys Res Commun. 1995; 209((1)): 218-26.

Takahashi T, Shirasawa T.. Molecular cloning of rat JAK3, a novel member of the JAK family of protein tyrosine kinases. FEBS Lett. 1994; 342((2)): 124-8.

Available Postdoctoral Position Details
Postdoctoral position is available immediately to study molecular pathways in endothelial vessel formation and also in endothelial cell damage and regeneration. Projects include: 1) Study to determine the role of receptor tyrosine phosphatase in endothelial vessel formation. 2) Animal study to investigate molecular mechanisms underlying diabetic endothelial dysfunction and unregulated angiogenesis. For further information, applicants should send a C.V. to: Takamune Takahashi, M.D., Ph.D. Assistant Professor of Medicine Division of Nephrology S-3223, Medical Center North, Nashville, TN 37232 Ph: 615 343 4312 Fax: 615 343 7156 E-mail: takamune.takahashi@vanderbilt.edu