Vanderbilt University School of
Haase, Volker H. , M.D.
Associate Professor of Medicine
Associate Professor of Cancer Biology
Associate Professor of Molecular Physiology and Biophysics
Krick-Brooks Chair in Nephrology
Phone Number: 615-343-7254
Division of Nephrology and Hypertension, Vanderbilt University Medical Center, C-3119A MCN 37232-2372
Molecular oxygen-sensing; the pVHL/HIF pathway; erythropoiesis; EPO; iron metabolism; glucose and fat metabolism; ischemic cell injury and regeneration; progression of chronic renal disease; von Hippel-Lindau disease (VHL); kidney cancer and renal cystogenesis; hepatic steatosis; conditional gene targeting technology and transgenesis; embryonic stem (ES) cells; mouse model systems.
The Haase laboratory studies the VHL/HIF oxygen-sensing pathway and uses conditional gene targeting technology and transgenesis, as well as biochemical and functional genomics approaches to define the specific roles of the von Hippel-Lindau (VHL) tumor suppressor and individual HIF transcription factors in tumorigenesis, acute ischemia and chronic hypoxic injury, as well as erythropoiesis and iron metabolism. Hypoxia-Inducible Factors HIF-1 and HIF-2 are oxygen-sensitive basic helix-loop-helix transcription factors, which regulate biological processes that facilitate both oxygen delivery and cellular adaptation to oxygen deprivation. HIFs consist of an oxygen-sensitive alpha-subunit, HIF-alpha and a constitutively expressed beta-subunit, HIF-beta, and regulate the expression of genes that are involved in energy metabolism, angiogenesis, erythropoiesis and iron metabolism, cell proliferation, apoptosis and other biological processes. Under conditions of normal oxygen tension HIF-alpha is hydroxylated and targeted for rapid proteasomal degradation by the VHL/E3-ubiquitin ligase. When cells experience hypoxia, HIF-alpha is stabilized and either dimerizes with HIF-beta in the nucleus to form transcriptionally active HIF executing the canonical hypoxia response, or it physically interacts with other non-HIF proteins, enabling convergence of HIF oxygen sensing with other signaling pathways. Since HIF increases the expression of cytoprotective factors and erythropoietin, pharmacologic inhibition of HIF-alpha degradation offers significant potential for the treatment of acute hypoxic injuries and anemia.
General Nephrology, Renal Anemia and Renal Metabolism.
Haase, VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev, 27(1), 41-53, 2013.
Haase, VH. Mechanisms of hypoxia responses in renal tissue. J Am Soc Nephrol, 24(4), 537-41, 2013.
Lin, Q, Huang, Y, Booth, CJ, Haase, VH, Johnson, RS, Celeste Simon, M, Giordano, FJ, Yun, Z. Activation of hypoxia-inducible factor-2 in adipocytes results in pathological cardiac hypertrophy. J Am Heart Assoc, 2(6), e000548, 2013.
Tak, E, Ridyard, D, Kim, JH, Zimmerman, M, Werner, T, Wang, XX, Shabeka, U, Seo, SW, Christians, U, Klawitter, J, Moldovan, R, Garcia, G, Levi, M, Haase, V, Ravid, K, Eltzschig, HK, Grenz, A. CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy. J Am Soc Nephrol, , , 2013.
Grenz, A, Bauerle, JD, Dalton, JH, Ridyard, D, Badulak, A, Tak, E, McNamee, EN, Clambey, E, Moldovan, R, Reyes, G, Klawitter, J, Ambler, K, Magee, K, Christians, U, Brodsky, KS, Ravid, K, Choi, DS, Wen, J, Lukashev, D, Blackburn, MR, Osswald, H, Coe, IR, N??rnberg, B, Haase, VH, Xia, Y, Sitkovsky, M, Eltzschig, HK. Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. J Clin Invest, 122(2), 693-710, 2012. PMCID:3266792
Haase, VH. Renal cancer: oxygen meets metabolism. Exp Cell Res, 318(9), 1057-67, 2012.
Haase, VH. Hypoxia-inducible factor signaling in the development of kidney fibrosis. Fibrogenesis Tissue Repair, 5 Suppl 1, S16, 2012.
Kapitsinou, PP, Jaffe, J, Michael, M, Swan, CE, Duffy, KJ, Erickson-Miller, CL, Haase, VH. Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury. Am J Physiol Renal Physiol, 302(9), F1172-9, 2012.
Kobayashi, H, Gilbert, V, Liu, Q, Kapitsinou, PP, Unger, TL, Rha, J, Rivella, S, Schl??ndorff, D, Haase, VH. Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury. J Immunol, 188(10), 5106-15, 2012.
Liu, Q, Davidoff, O, Niss, K, Haase, VH. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest, 122(12), 4635-44, 2012.
Park, SW, Kim, M, Kim, JY, Brown, KM, Haase, VH, D''Agati, VD, Lee, HT. Proximal tubule sphingosine kinase-1 has a critical role in A1 adenosine receptor-mediated renal protection from ischemia. Kidney Int, 82(8), 878-91, 2012.
Gurley, SB, Riquier-Brison, AD, Schnermann, J, Sparks, MA, Allen, AM, Haase, VH, Snouwaert, JN, Le, TH, McDonough, AA, Koller, BH, Coffman, TM. AT1A angiotensin receptors in the renal proximal tubule regulate blood pressure. Cell Metab, 13(4), 469-75, 2011.
Haase, VH. Angiotensin II: breathtaking in the renal medulla. Kidney Int, 79(3), 269-71, 2011.
Kapitsinou, PP, Liu, Q, Unger, TL, Rha, J, Davidoff, O, Keith, B, Epstein, JA, Moores, SL, Erickson-Miller, CL, Haase, VH. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood, 116(16), 3039-48, 2010 (see commentary by Terry Lappin in the same issue of Blood, see commentary in Kidney International - Journal Club: 78 (8), 717a??718, 2010. doi:10.1038/ki.2010.34) .
Bajwa, A, Jo, SK, Ye, H, Huang, L, Dondeti, KR, Rosin, DL, Haase, VH, Macdonald, TL, Lynch, KR, Okusa, MD. Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury. J Am Soc Nephrol, 21(6), 955-65, 2010.
Bielesz, B, Sirin, Y, Si, H, Niranjan, T, Gruenwald, A, Ahn, S, Kato, H, Pullman, J, Gessler, M, Haase, VH, Susztak, K. Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. J Clin Invest, 120(11), 4040-54, 2010. PMCID:2964979
Haase, VH. Hypoxic regulation of erythropoiesis and iron metabolism. Am J Physiol Renal Physiol, 299(1), F1-13, 2010.
Haase, VH. The sweet side of HIF. Kidney Int, 78(1), 10-3, 2010.
Hao, CM, Haase, VH. Sirtuins and their relevance to the kidney. J Am Soc Nephrol, 21(10), 1620-7, 2010.
Kapitsinou, PP, Haase, VH. HO-1 in control of a self-eating kidney. J Am Soc Nephrol, 21(10), 1600-2, 2010.
Lee, JJ, Natsuizaka, M, Ohashi, S, Wong, GS, Takaoka, M, Michaylira, CZ, Budo, D, Tobias, JW, Kanai, M, Shirakawa, Y, Naomoto, Y, Klein-Szanto, AJ, Haase, VH, Nakagawa, H. Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis. Carcinogenesis, 31(3), 427-34, 2010.
Seagroves, TN, Peacock, DL, Liao, D, Schwab, LP, Krueger, R, Handorf, CR, Haase, VH, Johnson, RS. VHL deletion impairs mammary alveologenesis but is not sufficient for mammary tumorigenesis. Am J Pathol, 176(5), 2269-82, 2010.
Wei, Q, Bhatt, K, He, HZ, Mi, QS, Haase, VH, Dong, Z. Targeted deletion of Dicer from proximal tubules protects against renal ischemia-reperfusion injury. J Am Soc Nephrol, 21(5), 756-61, 2010.
Weidemann, A, Krohne, TU, Aguilar, E, Kurihara, T, Takeda, N, Dorrell, MI, Simon, MC, Haase, VH, Friedlander, M, Johnson, RS. Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia, 58(10), 1177-85, 2010.
Welford, SM, Dorie, MJ, Li, X, Haase, VH, Giaccia, AJ. Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress. Mol Cell Biol, 30(19), 4595-603, 2010.
Rankin, EB, Rha, J, Selak, MA, Unger, TL, Keith, B, Liu, Q, Haase, VH. Hypoxia-inducible factor 2 regulates hepatic lipid metabolism. Mol Cell Biol, 29(16), 4527-38, 2009 (cover page feature). PMCID:2725738
Haase, VH. Pathophysiological Consequences of HIF Activation. Ann N Y Acad Sci, 1177, 57-65, 2009.
Haase, VH. Oxygen regulates epithelial-to-mesenchymal transition: insights into molecular mechanisms and relevance to disease. Kidney Int, 76(5), 492-9, 2009.
Haase, VH. The VHL tumor suppressor: master regulator of HIF. Curr Pharm Des, 15(33), 3895-903, 2009. PMCID:2769183
Weidemann, A, Kerdiles, YM, Knaup, KX, Rafie, CA, Boutin, AT, Stockmann, C, Takeda, N, Scadeng, M, Shih, AY, Haase, VH, Simon, MC, Kleinfeld, D, Johnson, RS. The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J Clin Invest, 119(11), 3373-83, 2009. PMCID:2769183
Boutin, AT, Weidemann, A, Fu, Z, Mesropian, L, Gradin, K, Jamora, C, Wiesener, M, Eckardt, KU, Koch, CJ, Ellies, LG, Haddad, G, Haase, VH, Simon, MC, Poellinger, L, Powell, FL, Johnson, RS. Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell, 133(2), 223-34, 2008. PMCID:2849644
Haase, VH. Hemoglobin in the kidney: breaking with traditional dogma. J Am Soc Nephrol, 19(8), 1440-1, 2008.
Higgins, DF, Kimura, K, Iwano, M, Haase, VH. Hypoxia-inducible factor signaling in the development of tissue fibrosis. Cell Cycle, 7(9), 1128-32, 2008. PMCID:2849644
Kapitsinou, PP, Haase, VH. The VHL tumor suppressor and HIF: insights from genetic studies in mice. Cell Death Differ, 15(4), 650-9, 2008. PMCID:2849644
Kimura, K, Iwano, M, Higgins, DF, Yamaguchi, Y, Nakatani, K, Harada, K, Kubo, A, Akai, Y, Rankin, EB, Neilson, EG, Haase, VH, Saito, Y. Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol, 295(4), F1023-9, 2008. PMCID:2725738
Maltzman, JS, Haase, VH. Low oxygen stimulates the immune system. Kidney Int, 73(7), 797-9, 2008.
Peng, M, Falk, MJ, Haase, VH, King, R, Polyak, E, Selak, M, Yudkoff, M, Hancock, WW, Meade, R, Saiki, R, Lunceford, AL, Clarke, CF, Gasser, DL. Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease. PLoS Genet, 4(4), e1000061, 2008. PMCID:2291193
Rankin, EB, Rha, J, Unger, TL, Wu, CH, Shutt, HP, Johnson, RS, Simon, MC, Keith, B, Haase, VH. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene, 27(40), 5354-8, 2008. PMCID:2575082
Shah, YM, Ito, S, Morimura, K, Chen, C, Yim, SH, Haase, VH, Gonzalez, FJ. Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology, 134(7), 2036-48, 2048.e1-3, 2008. PMCID:2533811
Blouw, B, Haase, VH, Song, H, Bergers, G, Johnson, RS. Loss of vascular endothelial growth factor expression reduces vascularization, but not growth, of tumors lacking the Von Hippel-Lindau tumor suppressor gene. Oncogene, 26(31), 4531-40, 2007.
Brukamp, K, Jim, B, Moeller, MJ, Haase, VH. Hypoxia and podocyte-specific Vhlh deletion confer risk of glomerular disease. Am J Physiol Renal Physiol, 293(4), F1397-407, 2007.
Higgins, DF, Kimura, K, Bernhardt, WM, Shrimanker, N, Akai, Y, Hohenstein, B, Saito, Y, Johnson, RS, Kretzler, M, Cohen, CD, Eckardt, KU, Iwano, M, Haase, VH. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest, 117(12), 3810-20, 2007. PMCID:2082142
Park, SK, Haase, VH, Johnson, RS. von Hippel Lindau tumor suppressor regulates hepatic glucose metabolism by controlling expression of glucose transporter 2 and glucose 6-phosphatase. Int J Oncol, 30(2), 341-8, 2007.
Peyssonnaux, C, Zinkernagel, AS, Schuepbach, RA, Rankin, E, Vaulont, S, Haase, VH, Nizet, V, Johnson, RS. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest, 117(7), 1926-32, 2007. PMCID:1884690
Rankin, EB, Biju, MP, Liu, Q, Unger, TL, Rha, J, Johnson, RS, Simon, MC, Keith, B, Haase, VH. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest, 117(4), 1068-77, 2007. PMCID:1838939
Wang, Y, Wan, C, Deng, L, Liu, X, Cao, X, Gilbert, SR, Bouxsein, ML, Faugere, MC, Guldberg, RE, Gerstenfeld, LC, Haase, VH, Johnson, RS, Schipani, E, Clemens, TL. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest, 117(6), 1616-26, 2007. PMCID:1878533
Ding, M, Cui, S, Li, C, Jothy, S, Haase, V, Steer, BM, Marsden, PA, Pippin, J, Shankland, S, Rastaldi, MP, Cohen, CD, Kretzler, M, Quaggin, SE. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med, 12(9), 1081-7, 2006.
Haase, VH. Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol, 291(2), F271-81, 2006.
Haase, VH. The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney Int, 69(8), 1302-7, 2006.
Liu, Y, Pop, R, Sadegh, C, Brugnara, C, Haase, VH, Socolovsky, M. Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo. Blood, 108(1), 123-33, 2006. PMCID:1895827
Rankin, EB, Tomaszewski, JE, Haase, VH. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res, 66(5), 2576-83, 2006.
Tang, N, Mack, F, Haase, VH, Simon, MC, Johnson, RS. pVHL function is essential for endothelial extracellular matrix deposition. Mol Cell Biol, 26(7), 2519-30, 2006. PMCID:1430327
Wang, J, Biju, MP, Wang, MH, Haase, VH, Dong, Z. Cytoprotective effects of hypoxia against cisplatin-induced tubular cell apoptosis: involvement of mitochondrial inhibition and p53 suppression. J Am Soc Nephrol, 17(7), 1875-85, 2006.
Biju, MP, Akai, Y, Shrimanker, N, Haase, VH. Protection of HIF-1-deficient primary renal tubular epithelial cells from hypoxia-induced cell death is glucose dependent. Am J Physiol Renal Physiol, 289(6), F1217-26, 2005.
Haase, VH. The VHL tumor suppressor in development and disease: functional studies in mice by conditional gene targeting. Semin Cell Dev Biol, 16(4-5), 564-74, 2005.
Karhausen, J, Haase, VH, Colgan, SP. Inflammatory hypoxia: role of hypoxia-inducible factor. Cell Cycle, 4(2), 256-8, 2005.
Mack, FA, Patel, JH, Biju, MP, Haase, VH, Simon, MC. Decreased growth of Vhl-/- fibrosarcomas is associated with elevated levels of cyclin kinase inhibitors p21 and p27. Mol Cell Biol, 25(11), 4565-78, 2005. PMCID:1140627
Neumann, AK, Yang, J, Biju, MP, Joseph, SK, Johnson, RS, Haase, VH, Freedman, BD, Turka, LA. Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci U S A, 102(47), 17071-6, 2005. PMCID:1287984
Rankin, EB, Higgins, DF, Walisser, JA, Johnson, RS, Bradfield, CA, Haase, VH. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol Cell Biol, 25(8), 3163-72, 2005. PMCID:1069599
Biju, MP, Neumann, AK, Bensinger, SJ, Johnson, RS, Turka, LA, Haase, VH. Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol Cell Biol, 24(20), 9038-47, 2004. PMCID:517905
Higgins, DF, Biju, MP, Akai, Y, Wutz, A, Johnson, RS, Haase, VH. Hypoxic induction of Ctgf is directly mediated by Hif-1. Am J Physiol Renal Physiol, 287(6), F1223-32, 2004.
Karhausen, J, Furuta, GT, Tomaszewski, JE, Johnson, RS, Colgan, SP, Haase, VH. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest, 114(8), 1098-106, 2004. PMCID:522241
Pfander, D, Kobayashi, T, Knight, MC, Zelzer, E, Chan, DA, Olsen, BR, Giaccia, AJ, Johnson, RS, Haase, VH, Schipani, E. Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development. Development, 131(10), 2497-508, 2004. PMCID:517905
Cramer, T, Yamanishi, Y, Clausen, BE, F??rster, I, Pawlinski, R, Mackman, N, Haase, VH, Jaenisch, R, Corr, M, Nizet, V, Firestein, GS, Gerber, HP, Ferrara, N, Johnson, RS. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell, 112(5), 645-57, 2003. PMCID:162224
Higgins, DF, Lappin, DW, Kieran, NE, Anders, HJ, Watson, RW, Strutz, F, Schlondorff, D, Haase, VH, Fitzpatrick, JM, Godson, C, Brady, HR. DNA oligonucleotide microarray technology identifies fisp-12 among other potential fibrogenic genes following murine unilateral ureteral obstruction (UUO): modulation during epithelial-mesenchymal transition. Kidney Int, 64(6), 2079-91, 2003. PMCID:1069599
Park, SK, Dadak, AM, Haase, VH, Fontana, L, Giaccia, AJ, Johnson, RS. Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1alpha (HIF-1alpha): role of cytoplasmic trapping of HIF-2alpha. Mol Cell Biol, 23(14), 4959-71, 2003. PMCID:162224
Haase, VH, Glickman, JN, Socolovsky, M, Jaenisch, R. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A, 98(4), 1583-8, 2001. PMCID:29300
Socolovsky, M, Nam, H, Fleming, MD, Haase, VH, Brugnara, C, Lodish, HF. Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood, 98(12), 3261-73, 2001.
Snijders, AJ, Ho, SC, Haase, VH, Pillai, S, Bernards, A. A lymphocyte-specific Ltk tyrosine kinase isoform is retained in the endoplasmic reticulum in association with calnexin. J Biol Chem, 272(2), 1297-301, 1997.
Haase VH, Schmidt EV, Wang T, Bernards A. Normal lymphopoiesis in transgenic mice overexpressing the ltk transmembrane tyrosine kinase. Transgenics, (1), 487-95, 1995.
Haase, VH, Trofatter, JA, MacCollin, M, Tarttelin, E, Gusella, JF, Ramesh, V. The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms. Hum Mol Genet, 3(3), 407-11, 1994.
Snijders, AJ, Haase, VH, Bernards, A. Four tissue-specific mouse ltk mRNAs predict tyrosine kinases that differ upstream of their transmembrane segment. Oncogene, 8(1), 27-35, 1993.
Trofatter, JA, MacCollin, MM, Rutter, JL, Murrell, JR, Duyao, MP, Parry, DM, Eldridge, R, Kley, N, Menon, AG, Pulaski, K, Haase, VH, Ambrose, CM, Munroe, D, Bove, C, Haines, JL, Martuza, RL, MAcDonald, ME, Seizinger, BR, Short, MP, Buckler, A, Gusella JF. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell, 72(5), 791-800, 1993.
Bernards, A, Haase, VH, Murthy, AE, Menon, A, Hannigan, GE, Gusella, JF. Complete human NF1 cDNA sequence: two alternatively spliced mRNAs and absence of expression in a neuroblastoma line. DNA Cell Biol, 11(10), 727-34, 1992.
Haase, VH, Snijders, AJ, Cooke, SM, Teng, MN, Kaul, D, Le Beau, MM, Bruns, GA, Bernards, A. Alternatively spliced ltk mRNA in neurons predicts a receptor with a larger putative extracellular domain. Oncogene, 6(12), 2319-25, 1991.
NIH-funded postdoctoral position: We are looking for highly motivated applicants, who would like to pursue a career in biomedical science and would like to work in a competitive field. A successful applicant will have excellent communication skills.
Research projects include:
a) characterization of mouse models of disrupted oxygen sensing,
b) identification, functional and molecular characterization of HIF target genes involved in cellular metabolism and hypoxic injury responses,
c) in vitro and in vivo investigations of HIF signaling in acute and chronic hypoxic injury.
Rotation students will participate in ongoing projects and will be exposed to a broad spectrum of molecular techniques, as well as in vivo work.
Vanderbilt University is committed to principles of equal opportunity and affirmative action.
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