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. Whereas evidence for a role of the adaptive immune system in arterial hypertension is accumulating, data about the contribution of the innate immune system, especially with respect to hypertensive glomerular injury, is still scarce. A hint for crucial involvement of innate immunity in hypertensive glomerular injury comes from observations in malignant nephrosclerosis. This catastrophic form of hypertensive renal injury is characterized by complement deposition and abundant cell infiltration into the kidney. It is yet unknown, why some patients with severe hypertension develop malignant nephrosclerosis and others with similar levels of blood pressure elevation do not. We hypothesize that components of innate immunity, such as complement, might be involved in the development of severe malignant nephrosclerosis. In the first two parts of this project, we will use two mouse models of hypertension to investigate the role dendritic cells and the complement system in hypertensive renal injury. In the third part of the project, we will analyze a mouse model of malignant nephrosclerosis to study the potential involvement of immune mechanisms in hypertensive glomerular injury and in the switch from “benign” blood pressure elevation to malignant hypertension with severe end-organ damage. In a translational approach, we will then evaluate the immune mechanisms identified in the mouse models in samples from patients with malignant nephrosclerosis. Our studies will contribute to a better understanding of innate immune mechanisms in hypertensive glomerular injury and identify underlying factors for the development of malignant nephrosclerosis in hypertensive patients.