The role of dendritic cells and complement in arterial hypertension and hypertensive end organ damage

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The importance of the immune system in the development of arterial hypertension has been recognized in the past decade. Dendritic cells, the most important professional antigen-presenting cells, play a key role in arterial hypertension. The mechanisms, how dendritic cells affect blood pressure and end organ damage, are still poorly understood. Dendritic cells express a functionally active mineralocorticoid receptor and show a strong expression of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2. The complement protein C3 also seems to play a role in arterial hypertension. Therefore, we have four goals in this project.1. The mineralocorticoid receptor plays an important role in cardiovascular diseases not only on renal epithelial cells but also on non-epithelial cells. Our data show that a selective knockout of the mineralocorticoid receptor in dendritic cells lowers blood pressure and reduces end organ damage. What is the significance of the mineralocorticoid receptor on dendritic cells and how does it affect blood pressure? What effects does it have in dendritic cells in the regulation of the salt balance in the kidney?2. Recent data show that intracellular C3 has metabolic functions. Using a C3 knockout mouse, a siRNA approach that selectively inhibits hepatic C3, and a C3 knockout in dendritic cells, we will examine the mechanisms by which C3 influences arterial hypertension and the metabolic effects of C3 in dendritic cells.3. Our preliminary work shows that deficiency of anaphylatoxin receptors has divergent effects in arterial hypertension. With the help of reporter and floxed knockout mice, we will elucidate the role and interactions of anaphylatoxin receptors among each other in arterial hypertension. In particular, we will investigate in vivo (including RNA-seq) and in vitro, which immunological and cell physiological effects the receptors have on dendritic cells in hypertension.4. Atypical hemolytic uremic syndrome is a complement-mediated disease that has clinical and morphological overlaps with malignant nephrosclerosis. The latter is the strongest kidney injury caused by arterial hypertension. We morphologically characterized human renal biopsies with malignant nephrosclerosis. Using complement mapping and a proteomic approach of tissue obtained by laser dissection microscopy from renal biopsies, we will investigate whether abnormalities in the complement system underlie the development of malignant nephrosclerosis.We expect to gain a much better understanding of the role of dendritic cells in the pathophysiology of arterial hypertension and to discover new therapeutic targets for patients with arterial hypertension and with malignant nephrosclerosis.