Research Report 2010 - MDC

Structure of the GroupDominik N. Müller(Delbrück Fellow)Group LeaderDr. Dominik N. MüllerScientistsDr. Petra GratzeDr. Heda KvakanDr. Verena FokuhlDr. Norbert HenkeDr. Fatimunnisa QadriAssociated ScientistsDr. Ralf DechendDr. Wolf-Hagen SchunckDr. Robert FischerGraduate StudentsUlrike MaschkeAnne KonkelTechnical AssistantsMay-Britt KöhlerJutta MeiselGabi N’diayeJuliane AndersManager of sponsored programsSusanne WisslerMechanisms of Hypertension-InducedTarget Organ DamageDominik N. Müller leads a group of young investigators pursuing the question of how hypertensioninduces target-organ damage. In a translational approach funded by an ECRC grant, Ralf Dechend(Helios Clinic) and Dominik Müller focus primarily on the placenta, heart and kidneys. The primarymediator that has captured their attention is the renin-angiotensin system. The group also cooperatesclosely with MDC scientists. The group has also been a resource for young clinicians and doctoralstudents beginning their careers in experimental cardiovascular research.The group collaborated with Michael Bader and OliverDaumke on the (pro)renin receptor, with Wolf-HagenSchunck and Robert Fischer (Charité) on target organprotective role of polyunsaturated fatty acid and theidentification eicosanoid receptors, with Ruth Schmidt-Ullrich and Claus Scheidereich on the role of NF-κB intarget organ damage, with Martin Zenke (Aachen) toexplore the role of the “inhibitor of differentiation 2”(ID2) in hypertension-induced kidney injury, and withMarkus Kleinewietfeld to elucidate the protective role ofregulatory T cells (Tregs) in hypertension-induced cardiacinjury. Finally, the group made the novel observationthat the human renin promulgates obesity in transgenicrats by inducing changes in energy metabolism.Immune mechanisms in hypertensionMice deficient for Id2(-/-) lack Langerhans and splenicCD8a+ dendritic cells, have reduced natural killer cells,and have altered CD8 T-cell memory. Petra Gratze andthe group tested the hypothesis that an alteration inthe number and quality of circulating blood cellscaused by Id2 deletion would ameliorate angiotensin(Ang) II-induced target-organ damage. Id2-/- micefailed to develop an increase in blood pressure wheninfused with Ang II and had no target-organ damage.The group conducted kidney (figure 1) and bone marrowtransplants that did not restore the sensitivity toAng II. They also found that vascular smooth musclecells from Id2-/- mice showed an antisenescence phenotype.The study identified a previously undefined rolefor Id2 in the pathogenesis of Ang II-induced hypertension.This role is being further explored.Heda Kvakan led the project studying the role ofimmunosuppressive CD4+CD25+ regulatory T (Treg)cells in the pathogenesis of hypertensive target organdamage. The group conducted adoptive transfer of Tregcells into Ang II-infused hypertensive mice. Treg cellrecipients exhibited improved cardiac hypertrophy andless cardiac fibrosis despite sustained hypertension.Amelioration of cardiac morphology was accompaniedby an improvement in arrhythmogenic electric remodeling,indicating the functional significance of theenhanced cardiac morphology. Pronounced connexin43 immunoreactivity was found at the lateral bordersof cardiomyocytes in Ang II-treated mice, implicatingthis gap-junction protein in the arrhythmias. In contrast,connexin 43 was restricted to the intercalateddisk regions in sham controls. Surprisingly, Ang II+Tregtreatedmice showed normal connexin 43 gap junctionprotein localization. Thus, Treg cells ameliorated cardiacdamage and accounted for the improved electricremodeling independently of blood pressure-loweringeffects. The results provide new insights into the pathogenesisof hypertensive cardiac damage and couldtherefore lead to new therapeutic approaches thatinvolve manipulation of the immune system.The (pro)renin receptorThe Müller laboratory collaborates with GenevieveNguyen (INSERM Paris), Michael Bader and Oliver36 Cardiovascular and Metabolic Disease Research