Research projects

Project leader: Duska Dragun
Co-workers: Aurélie Philippe, Rusan Catar, Nan Zhu, Daniel Postpieszala
Cooperations: H Heidecke, P Scheerer, P Hildebrand, M Szczepek, S Dowell (Stevenage)

The Angiotensin II type 1 (AT₁R) receptor belongs to the family of the G-Protein Coupled Receptors (GPCR). GPCR are known to modulate their structure according to the stimulation they encounter leading to the activation of different signaling pathways. AT₁R signals stimuli provided by its natural ligand angiotensin II (Ang II) and pathogenic IgG antibodies (AT₁R-Abs) in severe transplant and immune-mediated vasculopathies. Each stimulation triggers a different intracellular response, as we have shown in our previous publications. AT₁R is a well-established pharmacologic target for several inverse agonists; however the exact changes of the receptor allowing the integration of various stimuli and the activation of different cellular pathways are still unknown. To study differences in activation between Ang II and AT₁R-Abs, we developed a yeast model where the expression of a single human AT₁R is coupled to the yeast's growth response in absence of Histidine.

Project leader: Duska Dragun
Co-workers: Rusan Catar, Aurélie Philippe, Angelika Kusch, Isa Anett Hosp, Christian Lücht, Nan Zhu Cooperations: H Heidecke, P Scheerer, P Hildebrand, M Szczepek, R Schülein, H Biebermann

Antibody-mediated rejection remains an important cause of both short-term and long-term injury to renal and other solid organ allografts. The microvascular endothelium is a major target for antibodies. Our group has convincingly demonstrated in series of in vivo and in vitro experiments that antibodies directed against Angiotensin II type 1 receptor (AT₁R) and Endothelin-1 type A receptor (ETAR) play a pathophysiological role in both acute and chronic injury of kidney allografts. In the context of autoimmune disease AT₁R and ETAR determine pathological vascular remodeling by activation of inflammatory cytokines. During transplantation procedure, the homeostatic microenvironment is disrupted via trauma and ischemia resulting in the release of pro-inflammatory cytokines. This further enhances endothelial dysfunction by expression of G protein-coupled receptors (GPCR) on cell surface that render them targets for antibodies and/or effector cytotoxic CD8+ T cells that consecutively mediate injury and sustain a state of inflammation within the transplant.

Project leader: Duska Dragun
Co-workers: Angelika Kusch, Dennis Gürgen
Cooperations: Tobias Huber, Marijke Brink

Cardiac hypertrophy and therefor individual cell size of cardiomyocytes is dependent on coordination of increased protein synthesis and metabolism. Mechanistic target of rapamycin (mTOR) acts as a key regulator of cell growth and metabolism via two distinct multiprotein complexes mTORC1 and mTORC2. While mTORC1 facilitates the initiation of protein translation via activation of S6-kinase and the eukaryotic translation initiation factor 4E-binding protein 1 (4-EBP1) mTORC2 regulates cell fate, senescence and cytoskeletal organization through phosphorylation of its most prominent downstream effector protein kinase B (AKT). By the use of a DOCA-salt mouse model for cardio-renal interaction we investigated sex specific myocardial adaptation. Intrinsic mTORC1 and compensatory mTORC2 activation together with estrogen receptor beta (ERβ) function account for relative cardioprotection of female WT mice. ERβ deletion as well as mTORC1 blockade by systemic rapamycin administration induced dilative LV phenotype and precipitates myocardial fibrosis. Hence, balanced activation of mTOR signaling pathway components is instrumental for intrinsic female sex specific cardio protection whereas modulation of mTOR signaling with rapamycin results in beneficial outcome only in male mice.

Project leader: Duska Dragun, Wolf-Hagen Schunck
Co-workers: Mandy Fechner, Uwe Hoff, Dennis Gürgen
Cooperations: Toralf Niendorf, Tobias Huber

We established a new method enabling in vivo MRI monitoring of blood oxygenation (9.4 T small animal MR-scanner) with high spatiotemporal resolution during the initial I/R phase. In order to determine the timeline of key pathophysiologic changes we applied this new method and adapted our experimental setting to monitor how the EET-agonist may influence intrarenal oxygenation during the induction of ischemia and early reperfusion period.
Our long-term objective is to develop novel strategies for the prevention of acute kidney injury (AKI) based on a better understanding of intrinsic renoprotective mechanisms. Within the DFG funded Forschergruppe "FOR 1368 - Hemodynamic Mechanisms of Acute Kidney Injury" we identified opposing roles of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) in ischemia/reperfusion (I/R)-induced AKI. 20-HETE aggravated the injury by mediating persistent vasoconstriction and stimulating pro-inflammatory and pro-apoptotic pathways, whereas EETs acted beneficially by suppressing these early I/R-induced events. Furthermore, we choose a genomic approach to elucidate whether the lower enzymatic degradation of EETs to DHETs in soluble epoxide hydrolase (sEH) deficient mice also translates into a beneficial outcome in I/R induced AKI.