The innate immune response in hypertensive glomerular injury
Recent data suggest that the immune system contributes significantly to the pathogenesis of hypertension and hypertensive end-organ damage. Complement and dendritic cells play a central role in hypertension and hypertensive injury. The complement system serves as a powerful danger sensing system that protects the host from a hostile microbial environment, while maintaining proper tissue and organ function through effective clearance of altered or dying cells. However, recent data suggest that the so-called non-canonical complement and the intracellular complement (complosome) play an important role in cell homeostasis and metabolism (see Figure).
We hypothesize that components of immunity, such as dendritic cells and complement, might be involved in the development of hypertension and severe malignant nephrosclerosis. The anaphylatoxin receptors C3aR, C5aR1 and C5aR2 are important effectors of the complement system. They are predominantly expressed on dendritic cells, but their role in these cells is unknown.
In the first two parts of this project, we will use mouse models of hypertension to investigate the role dendritic cells and the complement system in hypertension and hypertensive renal injury.
In the third part of the project, we will evaluate in a translational approach the relevance of the immune mechanisms identified in mouse models for the pathogenesis of malignant nephrosclerosis in humans. This catastrophic form of hypertensive renal injury is characterized by complement deposition and cell infiltration into the kidney, however, it is yet unknown, why only some patients with severe hypertension actually develop malignant nephrosclerosis.
Our studies will contribute to a better understanding of immune mechanisms in hypertensive glomerular injury and identify underlying factors for the development of malignant nephrosclerosis in hypertensive patients.
Rosendahl A, Kabiri R, Bode M, Cai A, Klinge S, Ehmke H, Mittrücker HW, Wenzel UOBr J Pharmacol. 2018 Sep
Ahadzadeh E, Rosendahl A, Czesla D, Steffens P, Prüßner L, Meyer-Schwesinger C, Wanner N, Paust H, Huber T, Stahl R, Wiech T, Kurts C, Seniuk A, Ehmke H, Wenzel UAm J Physiol Renal Physiol. 2018 Sep
Wenzel UO, Bode M, Kurts C, Ehmke H.Br J Pharmacol. 2018 May
Wenzel UO, Bode M, Köhl J, Ehmke HAm J Physiol Heart Circ Physiol. 2017 Mar
Weiss S, Rosendahl A, Czesla D, Meyer-Schwesinger C, Stahl RA, Ehmke H, Kurts C, Zipfel PF, Köhl J, Wenzel UOAm J Physiol Renal Physiol. 2016 Jun