Acute Renal Failure

BIOGRAPHY

http://www.sfb423.uk-erlangen.de/e47/e140/index_eng.html

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 alpha-subunit and a constitutively expressed beta-subunit (ARNT). The two known alpha-subunits (HIF-1alpha and HIF-2alpha) 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.

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