| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
|
FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online December 17, 2002 as doi:10.1096/fj.02-0445fje. |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
in distinct cell populations of different organs1
Departments of
* Nephrology and Medical Intensive Care,
Anatomy, and
Cell and Neurobiology, Charité, Humboldt University Berlin, Germany; and
Wellcome Trust Centre for Human Genetics, University of Oxford, Great Britain
2Correspondence: Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow Klinikum, Humboldt Universität Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: kai-uwe.eckardt{at}charite.de
SPECIFIC AIMS
This study was performed to establish the organ distribution, cellular sites of expression, and hypoxic inducibility of the transcriptional regulator hypoxia-inducible factor (HIF)-2
in vivo. HIF-2 and HIF-1 are structurally related isoforms of the oxygen-regulated subunit of the heterodimeric HIF transcription factor, which plays a key role in cellular adaptation to hypoxia. Both subunits are widely expressed in cell lines. Genetic disruption of either impairs embryonic development, indicating that functional overlap is limited. HIF-2 has been implicated in neo-angiogenesis and tumor growth, but in normal tissues the potential for induction of HIF-2 and its functional relevance has so far been unknown.
PRINCIPAL FINDINGS
We analyzed HIF-2 expression in control and hypoxic adult rats exposed to either normobaric hypoxia (8% O2) or functional anemia induced by carbon monoxide (CO, 0.1%). Tissues were assayed for HIF-2 mRNA expression (RNase protection assay) and for protein accumulation (immunoblotting and immunohistochemistry (IHC)), using two specific polyclonal antibodies raised against rodent HIF-2.
1. Healthy rats kept under standard conditions show no HIF-2 protein expression
Under baseline conditions, HIF-2 was not or was barely detectable on immunoblots (Fig. 1
A, control lane). Accordingly, IHC did not give a specific signal at baseline in any of the organs assayed: kidney, liver, duodenum, pancreas, heart, brain, and lung (Fig. 2
, left column).
|
|
2. Systemic hypoxia induces HIF-2 in all organs
Hypoxic rats showed a marked induction of HIF-2 protein in all organs assayed by immunoblotting. Comparing normobaric hypoxia (8% O2) and functional anemia (0.1% CO), there was a much stronger induction with CO. This difference may reflect differences in protein preservation, as stimulation with CO persists during the period between termination of exposure and organ harvest, so that reoxygenation is avoided. Differences between both stimuli were not so obvious when assayed by IHC, where more rapid and efficient tissue preservation was achieved using perfusion fixation. Stimulus-dependent differences were also less pronounced when studying induction in kidneys of the HIF target gene erythropoietin.
3. HIF-2 protein accumulates progressively for up to 6 h of stimulation
Time kinetics under CO showed continuously increasing levels of HIF-2 in all organs (Fig. 1A
). After 1 h, an induction already was visible in most organs; continued exposure led to a progressive increase of protein levels for up to 6 h. Exposure for 12 h showed a reduction of HIF-2 protein abundance compared with 6 h.
4. Levels of HIF-2 accumulation vary widely between organs
Comparing the levels of (CO stimulated) HIF-2 by immunoblotting, the strongest induction could be seen in the liver, followed by kidney, duodenum, brain, heart, and lung (Fig. 1B
). Contrary to all other organs investigated the lung showed a more pronounced induction of HIF-2 when exposed to normobaric hypoxia compared with CO.
5. Within each organ HIF-2 is induced in distinct cell populations
IHC of tissues exposed to functional anemia or normobaric hypoxia showed nuclear accumulation of HIF-2 in all organs investigated. The pattern of cells staining positive differed between tissues. In kidney, brain, and pancreas, exclusively nonparenchymal expression was seen. Liver and intestine showed a predominant parenchymal expression, whereas the heart displayed an equal distribution of signals between cardiomyocytes and stromal cells (Fig. 2)
. In the liver, HIF-2 expression increased toward the center of the liver lobules. In brain, HIF-2 was induced in non-neuronal cells and capillary endothelial cells.
6. HIF-2 mRNA levels in different organs show a >10-fold difference
Assessment of mRNA abundance showed a marked expression of HIF-2 in all organs at baseline. Lowest levels were found in duodenum and brain. Compared to the level in duodenum, the relative abundance of HIF-2 mRNA was 1.7-fold in kidney, 2.8-fold in liver, 3.4-fold in heart, and 13.3-fold in lung.
7. Hypoxia has little effect on HIF-2 mRNA levels
Exposure of animals to CO (6 h) did not lead to a significant increase in HIF-2 mRNA abundance. Merely the liver showed a moderate, 2.5-fold induction compared with baseline.
CONCLUSIONS AND SIGNIFICANCE
Showing that the HIF-2 isoform of the HIF transcription factor family is markedly up-regulated in different organs under conditions of systemic hypoxia, this study indicates that HIF-2 plays a widespread role in transcriptional adaptation to hypoxia in adult organisms. However, within different organs, nuclear accumulation of HIF-2 is not ubiquitous and is confined to distinct cell types, which are only in part consistent across different tissues. Widespread expression in microvascular endothelial cells in virtually all organs investigated supports a significant role of HIF-2 in an endothelial response to hypoxia, which was already assumed when this molecule was originally termed endothelial PAS protein (Fig. 2
, Fig. 3
). Clearly, however, HIF-2 is not endothelial specific, since significant accumulation also occurred in parenchymal cells of some, albeit not all tissues.
|
In vitro studies showed that regulation of HIF subunits occurs primarily through changes in protein stability. In the presence of molecular oxygen distinct proline residues of HIF are hydroxylated, leading to ubiquitylation and proteasomal degradation (Fig. 3)
. Whether HIF mRNA levels are influenced by oxygen has been controversial. Comparison of HIF-2 mRNA and protein levels under baseline conditions and after 6 h of hypoxia reveals that the early induction of HIF-1 is unrelated to changes in HIF-2 mRNA abundance, supporting the view that regulation in vivo is primarily through post-translational mechanisms. There is no consistent evidence that the level of baseline HIF-2 mRNA determines the amount of HIF-2 protein that accumulates in hypoxia.
In support of the direct influence of oxygen tensions on HIF regulation, an association of HIF-2 induction with local oxygen gradients is apparent in some tissues. The liver shows a clear zonal distribution, matching the known decrease in oxygen tensions from the periportal fields toward the center of liver lobules (Fig. 2B
). In the lung, in contrast to all other organs investigated, a significant qualitative difference was found between anemic and hypoxic hypoxia in that only the latter strongly induced HIF-2 in pneumocytes. This is concordant with the fact that alveolar cells are supplied with oxygen from the inspired gas rather than through blood oxygen transport.
Even though reduced oxygenation activates HIF-2, there is an apparent paradox. Under the conditions of systemic hypoxia used in this study, oxygen tensions in some tissues most likely remain higher than in other areas of the body under "normoxic" baseline conditions. Even so, no basal expression of HIF-2 was observed at any site, not even in the renal papilla. These data argue strongly that HIF activation in vivo is not invariably linked to a specific oxygen concentration in all cells. Rather, the cellular oxygen response operates at different levels of sensitivity in different cells and tissues. In keeping with the operation of adaptive processes, we found a down-regulation of HIF-2 protein levels with prolonged hypoxia. The level at which this is achieved is not yet clear. Two of the three prolyl hydroxylases identified as responsible for HIF hydroxylation are inducible by hypoxia, and this response could form the basis of a negative feedback regulation.
Comparing results of the present investigation with recent data on the regulation of HIF-1 in mice reveals similarities but also several important differences. First, HIF-1 is already expressed under normoxic baseline conditions, which contrasts with the expression of HIF-2. Second, HIF-1 induction in kidney and liver was only transient and had disappeared after 3 h, whereas HIF-2 expression is sustained for > 6 h in all organs studied. Third, at least in the liver and kidney, more severe hypoxia (6% O2) was required to induce HIF-1 than HIF-2. Fourth, the lung differs from all other organs in that we could demonstrate its ability to induce HIF-2, whereas HIF-1 was undetectable even at 6% ambient oxygen. Fifth, within organs expressing both HIF isoforms, the overlap of cellular expression is limited. Hepatocytes, cardiomyocytes, and myocardial endothelial cells seem to respond to hypoxia with up-regulation of HIF-1 and HIF-2, whereas in kidney and brain, both isoforms are inducible in entirely different cell populations. In both organs, HIF-2 was confined to nonparenchymal cells, whereas HIF-1 is expressed in renal tubuli and neuronal cells.
These findings indicate that although the oxygen-sensing mechanism involving oxygen-dependent hydroxylation of HIF subunits is probably universally operating in cells and highly conserved during evolution, additional regulatory steps appear to operate that determine which of the alternate subunits is induced and at a which concentration of molecular oxygen. It is tempting to speculate that the differential expression of HIF-1 and HIF-2 conveys target gene specificity. Unraveling both aspects will be essential to further understand the complexity of tissue responses to hypoxia and may be crucial in order to obtain benefit from manipulating a pathway with such pleiotropic actions.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0445fje; to cite this article, use FASEB J. (December 17, 2002) 10.1096/fj.02-0445fje 
This article has been cited by other articles:
|
|
 |
|
  D. P. Gale, S. K. Harten, C. D. L. Reid, E. G. D. Tuddenham, and P. H. Maxwell Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2{alpha} mutation Blood, August 1, 2008; 112(3): 919 - 921. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yamashita, K. Ohneda, M. Nagano, C. Miyoshi, N. Kaneko, Y. Miwa, M. Yamamoto, O. Ohneda, and Y. Fujii-Kuriyama Hypoxia-inducible Transcription Factor-2{alpha} in Endothelial Cells Regulates Tumor Neovascularization through Activation of Ephrin A1 J. Biol. Chem., July 4, 2008; 283(27): 18926 - 18936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Berchner-Pfannschmidt, S. Frede, C. Wotzlaw, and J. Fandrey Imaging of the hypoxia-inducible factor pathway: insights into oxygen sensing Eur. Respir. J., July 1, 2008; 32(1): 210 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Lechler, X. Wu, W. Bernhardt, V. Campean, S. Gastiger, T. Hackenbeck, B. Klanke, A. Weidemann, C. Warnecke, K. Amann, et al. The Tumor Gene Survivin Is Highly Expressed in Adult Renal Tubular Cells: Implications for a Pathophysiological Role in the Kidney Am. J. Pathol., November 1, 2007; 171(5): 1483 - 1498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ditting, K. F. Hilgers, A. Stetter, P. Linz, C. Schonweiss, and R. Veelken Renal sympathetic nerves modulate erythropoietin plasma levels after transient hemorrhage in rats Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1099 - F1106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Forooghian, R. Razavi, and L. Timms Hypoxia-inducible factor expression in human RPE cells Br. J. Ophthalmol., October 1, 2007; 91(10): 1406 - 1410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Baranova, L. F. Miranda, P. Pichiule, I. Dragatsis, R. S. Johnson, and J. C. Chavez Neuron-Specific Inactivation of the Hypoxia Inducible Factor 1{alpha} Increases Brain Injury in a Mouse Model of Transient Focal Cerebral Ischemia J. Neurosci., June 6, 2007; 27(23): 6320 - 6332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhu, Y. Zhang, B. A. Ojwang, M. A. Brantley Jr, and J. M. Gidday Long-Term Tolerance to Retinal Ischemia by Repetitive Hypoxic Preconditioning: Role of HIF-1{alpha} and Heme Oxygenase-1 Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1735 - 1743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Kojima, T. Tanaka, R. Inagi, H. Kato, T. Yamashita, A. Sakiyama, O. Ohneda, N. Takeda, M. Sata, T. Miyata, et al. Protective Role of Hypoxia-Inducible Factor-2{alpha} against Ischemic Damage and Oxidative Stress in the Kidney J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1218 - 1226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Y. Zhu, E. Daghini, A. R. Chade, C. Napoli, E. L. Ritman, A. Lerman, and L. O. Lerman Simvastatin Prevents Coronary Microvascular Remodeling in Renovascular Hypertensive Pigs J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1209 - 1217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Bernhardt, M. S. Wiesener, A. Weidemann, R. Schmitt, W. Weichert, P. Lechler, V. Campean, A. C. M. Ong, C. Willam, N. Gretz, et al. Involvement of Hypoxia-Inducible Transcription Factors in Polycystic Kidney Disease Am. J. Pathol., March 1, 2007; 170(3): 830 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gruber, C.-J. Hu, R. S. Johnson, E. J. Brown, B. Keith, and M. C. Simon Acute postnatal ablation of Hif-2{alpha} results in anemia PNAS, February 13, 2007; 104(7): 2301 - 2306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nangaku The Heat Is On: An Expanding Role for Hypoxia-Inducible Factors in Kidney Transplantation J. Am. Soc. Nephrol., January 1, 2007; 18(1): 13 - 15. [Full Text] [PDF]
|
|
|
|
|
|
C. Rosenberger, J. Pratschke, B. Rudolph, S. N. Heyman, R. Schindler, N. Babel, K.-U. Eckardt, U. Frei, S. Rosen, and P. Reinke Immunohistochemical Detection of Hypoxia-Inducible Factor-1{alpha} in Human Renal Allograft Biopsies J. Am. Soc. Nephrol., January 1, 2007; 18(1): 343 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. H. Haase Hypoxia-inducible factors in the kidney Am J Physiol Renal Physiol, August 1, 2006; 291(2): F271 - F281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Bernhardt, V. Campean, S. Kany, J.-S. Jurgensen, A. Weidemann, C. Warnecke, M. Arend, S. Klaus, V. Gunzler, K. Amann, et al. Preconditional Activation of Hypoxia-Inducible Factors Ameliorates Ischemic Acute Renal Failure J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1970 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zheng, J. L. Ruas, R. Cao, F. A. Salomons, Y. Cao, L. Poellinger, and T. Pereira Cell-Type-Specific Regulation of Degradation of Hypoxia-Inducible Factor 1{alpha}: Role of Subcellular Compartmentalization Mol. Cell. Biol., June 15, 2006; 26(12): 4628 - 4641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-J. Hu, S. Iyer, A. Sataur, K. L. Covello, L. A. Chodosh, and M. C. Simon Differential Regulation of the Transcriptional Activities of Hypoxia-Inducible Factor 1 Alpha (HIF-1{alpha}) and HIF-2{alpha} in Stem Cells. Mol. Cell. Biol., May 1, 2006; 26(9): 3514 - 3526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Calvani, A. Rapisarda, B. Uranchimeg, R. H. Shoemaker, and G. Melillo Hypoxic induction of an HIF-1{alpha}-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells Blood, April 1, 2006; 107(7): 2705 - 2712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. Rankin, J. E. Tomaszewski, and V. H. Haase Renal cyst development in mice with conditional inactivation of the von hippel-lindau tumor suppressor. Cancer Res., March 1, 2006; 66(5): 2576 - 2583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Covello, J. Kehler, H. Yu, J. D. Gordan, A. M. Arsham, C.-J. Hu, P. A. Labosky, M. C. Simon, and B. Keith HIF-2{alpha} regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes & Dev., March 1, 2006; 20(5): 557 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nangaku Chronic Hypoxia and Tubulointerstitial Injury: A Final Common Pathway to End-Stage Renal Failure J. Am. Soc. Nephrol., January 1, 2006; 17(1): 17 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Biju, Y. Akai, N. Shrimanker, and V. H. Haase Protection of HIF-1-deficient primary renal tubular epithelial cells from hypoxia-induced cell death is glucose dependent Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1217 - F1226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. H Maxwell Hypoxia-inducible factor as a physiological regulator Exp Physiol, November 1, 2005; 90(6): 791 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Helton, J. Cui, J. R. Scheel, J. A. Ellison, C. Ames, C. Gibson, B. Blouw, L. Ouyang, I. Dragatsis, S. Zeitlin, et al. Brain-Specific Knock-Out of Hypoxia-Inducible Factor-1{alpha} Reduces Rather Than Increases Hypoxic-Ischemic Damage J. Neurosci., April 20, 2005; 25(16): 4099 - 4107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. B. Rankin, D. F. Higgins, J. A. Walisser, R. S. Johnson, C. A. Bradfield, and V. H. Haase Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice Mol. Cell. Biol., April 15, 2005; 25(8): 3163 - 3172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Wang, D. A. Davis, M. Haque, L. E. Huang, and R. Yarchoan Differential Gene Up-Regulation by Hypoxia-Inducible Factor-1{alpha} and Hypoxia-Inducible Factor-2{alpha} in HEK293T Cells Cancer Res., April 15, 2005; 65(8): 3299 - 3306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Scortegagna, K. Ding, Q. Zhang, Y. Oktay, M. J. Bennett, M. Bennett, J. M. Shelton, J. A. Richardson, O. Moe, and J. A. Garcia HIF-2{alpha} regulates murine hematopoietic development in an erythropoietin-dependent manner Blood, April 15, 2005; 105(8): 3133 - 3140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Covello, M. C. Simon, and B. Keith Targeted Replacement of Hypoxia-Inducible Factor-1{alpha} by a Hypoxia-Inducible Factor-2{alpha} Knock-in Allele Promotes Tumor Growth Cancer Res., March 15, 2005; 65(6): 2277 - 2286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Eisenhofer, T-T Huynh, K Pacak, F M Brouwers, M M Walther, W M Linehan, P J Munson, M Mannelli, D S Goldstein, and A G Elkahloun Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome Endocr. Relat. Cancer, December 1, 2004; 11(4): 897 - 911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Biju, A. K. Neumann, S. J. Bensinger, R. S. Johnson, L. A. Turka, and V. H. Haase Vhlh Gene Deletion Induces Hif-1-Mediated Cell Death in Thymocytes Mol. Cell. Biol., October 15, 2004; 24(20): 9038 - 9047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-Y. Zhu, A. R. Chade, M. Rodriguez-Porcel, M. D. Bentley, E. L. Ritman, A. Lerman, and L. O. Lerman Cortical Microvascular Remodeling in the Stenotic Kidney: Role of Increased Oxidative Stress Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1854 - 1859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.J. Harvey, K.L. Kind, M. Pantaleon, D.T. Armstrong, and J.G. Thompson Oxygen-Regulated Gene Expression in Bovine Blastocysts Biol Reprod, October 1, 2004; 71(4): 1108 - 1119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fukasawa, T. Tsuchiya, E. Takayama, N. Shinomiya, K. Uyeda, R. Sakakibara, and S. Seki Identification and Characterization of the Hypoxia-Responsive Element of the Human Placental 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase Gene J. Biochem., September 1, 2004; 136(3): 273 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Tissot van Patot, J. Bendrick-Peart, V. E. Beckey, N. Serkova, and L. Zwerdlinger Greater vascularity, lowered HIF-1/DNA binding, and elevated GSH as markers of adaptation to in vivo chronic hypoxia Am J Physiol Lung Cell Mol Physiol, September 1, 2004; 287(3): L525 - L532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Acker and H. Acker Cellular oxygen sensing need in CNS function: physiological and pathological implications J. Exp. Biol., August 15, 2004; 207(18): 3171 - 3188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Uchida, F. Rossignol, M. A. Matthay, R. Mounier, S. Couette, E. Clottes, and C. Clerici Prolonged Hypoxia Differentially Regulates Hypoxia-inducible Factor (HIF)-1{alpha} and HIF-2{alpha} Expression in Lung Epithelial Cells: IMPLICATION OF NATURAL ANTISENSE HIF-1{alpha} J. Biol. Chem., April 9, 2004; 279(15): 14871 - 14878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-J. Hu, L.-Y. Wang, L. A. Chodosh, B. Keith, and M. C. Simon Differential Roles of Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}) and HIF-2{alpha} in Hypoxic Gene Regulation Mol. Cell. Biol., December 15, 2003; 23(24): 9361 - 9374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Bruick Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor Genes & Dev., November 1, 2003; 17(21): 2614 - 2623. [Full Text] [PDF]
|
|
|
|
|
|
P. Maxwell HIF-1: An Oxygen Response System with Special Relevance to the Kidney J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2712 - 2722. [Full Text] [PDF]
|
|
|
|
|
|
P. B. Freeburg and D. R. Abrahamson Hypoxia-Inducible Factors and Kidney Vascular Development J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2723 - 2730. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Cuevas, R. Hernandez-Alcoceba, J. Aragones, S. Naranjo-Suarez, M. C. Castellanos, M. A. Esteban, S. Martin-Puig, M. O. Landazuri, and L. del Peso Specific Oncolytic Effect of a New Hypoxia-Inducible Factor-Dependent Replicative Adenovirus on von Hippel-Lindau-Defective Renal Cell Carcinomas Cancer Res., October 15, 2003; 63(20): 6877 - 6884. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
