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Regulation and relevance of the hypoxia-inducible transcription
Research Focus
Hypoxia plays an important role in the pathophysiology of renal injuries. Acute renal failure is associated with impaired oxygen supply due to a diminished blood flow, resulting either from a critical drop in renal perfusion pressure or from injury to the renal vasculature. Chronic kidney disease is accompanied by a rarefication of renal blood vessels, in particular of the postglomerular, peritubular capillaries. Rarefication of postglomerular vessels is associated by increasing tubulointerstitial fibrosis and thus aggravation of ischemia. However, the underlying molecular mechanisms and the consequences of oxygen deprivation in the kidney are still incompletely understood. In recent years it has become clear that hypoxia is not only associated with energy deprivation but involves active gene regulation. In particular, the Hypoxia-Inducible-Factor (HIF) is a transcription factor which has been identified to play a major role in regulating genes involved in angiogenesis, glycolysis, cell death / survival decisions and other metabolic responses to hypoxia. HIF is a dimer, consisting of an oxygen regulated α-subunit and a constitutively expressed ß-subunit (ARNT). The two known α-subunits (HIF-1α and HIF-2α) are hydroxylated in the presence of oxygen and are then recognized by the von Hippel-Lindau protein, which targets them for ubiquitination and subsequent proteasomal degradation. In hypoxia, no hydroxylation occurs, HIF accumulates in the cell and then enhances transcription of its various target genes.
Recently, 3 specific enzymes have been identified which hydroxylate HIF and thus control its cellular level and hypoxic transcription. These Prolyl-Hydroxylase-Domain enzymes (PHD1-3) therefore reflect cellular oxygen sensors and have a key position in the control of hypoxic organ adaptation. We have previously shown that inhibition of PHDs by enzyme inhibitors can amend kidney function in experimental acute renal failure. Our present studies aim to characterize expression and regulation of the 3 PHDs in the kidney. Analyses will include isolated tubular kidney cells and will be extended to the study of rodent kidneys in vivo. Functional investigations will in part be performed using genetically modified animals to assess regulatory feed back loops of the different HIF and PHD isoforms. Models of acute and of chronic renal failure will finally be used to further characterize the oxygen sensing mechanism in the kidney and to define potential protective effects of modulating the HIF/PHD system.
Principal Investigator(s)
Kai-Uwe Eckardt, Prof. Dr. med.
Address:
Medizinische Klinik 4, Nephrologie und Hypertensiologie
Krankenhausstr. 12, 91054 Erlangen
Email: Kai-Uwe.Eckardt@uk-erlangen.de
University education:
1985 MD thesis Department of Genetics, University of Münster
1993 Habilitation, Faculty of Science, University of Regensburg
1986 Dep. of Pathology University Münster and Internal Medicine, University Hannover
1987-1991 Postdoctoral Fellow, Institute of Physiology, University Zürich
1991 EMBO fellow , Dep. of Molecular Medicine, University of Oxford, UK
1991-1993 Institute of Physiology, University of Regensburg
1993 – 2003 Nephrology and Intensive Care Med., Charité, Humboldt-University, Berlin
Faculty positions:
1993 Assistant Professor, University of Regensburg
2001 Associate Professor, Charité, Humboldt University
Since 2004 Head of the Department of Nephrology and Hypertension, University of Erlangen-Nuremberg
Principal Investigator(s)
Carsten Willam, PD Dr. med.
Address:
Medizinische Klinik 4, Nephrologie und Hypertensiologie
Krankenhausstr. 12, 91054 Erlangen
Email: carsten.willam@uk-erlangen.de
University education:
1995 MD thesis, Charité, Humboldt-University, Berlin
1995 – 2004 Dep. Nephrology and Intensive Care Medicine, Charité, Humboldt-University, Berlin
2000 – 2002 Research Fellow, Wellcome Trust Centre for Human Genetics, Oxford, UK
since 2004 Dep. of Nephrology and Hypertension, University of Erlangen-Nuremberg
Keywords
Kidney disease, hypoxia, ischemia, Hypoxia Inducible Factor, Prolyl hydroxylases, acute renal failure.
Collaborations
Patrick Maxwell, London, UK
Christopher Pugh and Peter J. Ratcliffe, Oxford, UK
Randall Johnson, San Diego, USA
Volker Haase, Philadelphia, USA
Peter Schnülle, Mannheim
List of current publications
Schietke R, Warnecke C, Wacker I, Schödel J, Mole DR, Campean V, Amann K, Goppelt-Struebe M, Behrens J, Eckardt KU, Wiesener MS. The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1. J Biol Chem. 2010 Feb 26;285(9):6658-69.
Bernhardt WM, Gottmann U, Doyon F, Buchholz B, Campean V, Schödel J, Reisenbuechler A, Klaus S, Arend M, Flippin L, Willam C, Wiesener MS, Yard B, Warnecke C, Eckardt KU. Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model. Proc Natl Acad Sci U S A. 2009 Nov 23.
Volke M, Gale DP, Maegdefrau U, Schley G, Klanke B, Bosserhoff AK, Maxwell PH, Eckardt KU, Warnecke C. Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia-inducible factors. PLoS One. 2009 Nov 18;4(11):e7875.
Tanaka T, Wiesener M, Bernhardt W, Eckardt KU, Warnecke C. The human HIF (hypoxia-inducible factor)-3alpha gene is a HIF-1 target gene and may modulate hypoxic gene induction. Biochem J. 2009 Oct 23;424(1):143-51.
Schödel J, Klanke B, Weidemann A, Buchholz B, Bernhardt W, Bertog M, Amann K, Korbmacher C, Wiesener M, Warnecke C, Kurtz A, Eckardt KU, Willam C. HIF-prolyl hydroxylases in the rat kidney: physiologic expression patterns and regulation in acute kidney injury. Am J Pathol. 2009, 174(5):1663-74.
Eckardt KU. Frontiers in the pathogenesis of kidney disease. J Mol Med. 2009 Sep;87(9):837-9.
Wiesener MS, Maxwell PH, Eckardt KU. Novel insights into the role of the tumor suppressor von Hippel Lindau in cellular differentiation, ciliary biology, and cyst repression. J Mol Med. 2009 Sep;87(9):871-7.
Hackenbeck T, Knaup KX, Schietke R, Schödel J, Willam C, Wu X, Warnecke C, Eckardt KU, Wiesener MS. HIF-1 or HIF-2 induction is sufficient to achieve cell cycle arrest in NIH3T3 mouse fibroblasts independent from hypoxia. Cell Cycle. 2009, 8(9):1386-95.
Knaup KX, Jozefowski K, Schmidt R, Bernhardt WM, Weidemann A, Juergensen JS, Warnecke C, Eckardt KU, Wiesener MS. Mutual regulation of hypoxia-inducible factor and mammalian target of rapamycin as a function of oxygen availability. Mol Cancer Res. 2009 Jan;7(1):88-98.
Bernhardt WM, Eckardt KU. Physiological basis for the use of erythropoietin in critically ill patients at risk for acute kidney injury. Curr Opin Crit Care. 2008, 14(6):621-6.
Rosenberger C, Rosen S, Shina A, Frei U, Eckardt KU, Flippin LA, Arend M, Klaus SJ, Heyman SN. Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney. Nephrol Dial Transplant. 2008, 23(11):3472-8.
Warnecke C, Weidemann A, Volke M, Schietke R, Wu X, Knaup KX, Hackenbeck T, Bernhardt W, Willam C, Eckardt KU, Wiesener MS. The specific contribution of hypoxia-inducible factor-2alpha to hypoxic gene expression in vitro is limited and modulated by cell type-specific and exogenous factors. Exp Cell Res. 2008, 314(10):2016-27.
Jantsch J, Chakravortty D, Turza N, Prechtel AT, Buchholz B, Gerlach RG, Volke M, Gläsner J, Warnecke C, Wiesener MS, Eckardt KU, Steinkasserer A, Hensel M, Willam C. Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J Immunol. 2008, 180(7):4697-705.
Weidemann A, Bernhardt WM, Klanke B, Daniel C, Buchholz B, Câmpean V, Amann K, Warnecke C, Wiesener MS, Eckardt KU, Willam C. HIF Activation Protects From Acute Kidney Injury. J Am Soc Nephrol. 2008, 19(3):486-94.
Aragonés J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Lemieux H, Jeoung NH, Lambrechts D, Bishop T, Lafuste P, Diez-Juan A, Harten SK, Van Noten P, De Bock K, Willam C, Tjwa M, Grosfeld A, Navet R, Moons L, Vandendriessche T, Deroose C, Wijeyekoon B, Nuyts J, Jordan B, Silasi-Mansat R, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B, Gorus F, Buyse J, Sluse F, Harris RA, Gnaiger E, Hespel P, Van Hecke P, Schuit F, Van Veldhoven P, Ratcliffe P, Baes M, Maxwell P, Carmeliet P. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet. 2008, 40(2):170-80.
Weidemann A, Klanke B, Wagner M, Volk T, Willam C, Wiesener MS, Eckardt KU, Warnecke C. Hypoxia, via stabilization of the hypoxia-inducible factor HIF-1alpha, is a direct and sufficient stimulus for brain-type natriuretic peptide induction. Biochem J. 2008, 409(1):233-42.
