New pharmacological targets in arterial hypertension and hypertensive nephropathy

• Applicant: Professor Dr. Ulrich Wenzel
• Subject Area: Nephrology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 434162701

Recent clinical advances have highlighted the role of complement activation and the aldosterone system in renal disease. Based on our observations, made in studies funded through WE 1688/19-1, we are now setting two preclinical/translational goals: 1. The complement factor C3 is upregulated in the kidney in tubular cells in human and murine hypertensive nephropathy. Global C3 deficiency lowers albuminuria. We will examine the effect of a selective blockade of tubular compared to hepatic C3 on albuminuria. We will also examine whether C3 blockade is also protective in non-hypertensive albuminuria. C3b is a cleavage product of C3 and, after binding to complement factor B (CFB), forms the C3bBb convertase. The specific role of CFB and, thus, the C3bBb convertase in albuminuria will be examined by inducing hypertension in a CFB-deficient mouse. 2. Knockout of the mineralocorticoid receptor in CD11c+ dendritic cells lowers hypertension and end organ damage. The mechanisms are not understood. The used CD11cCre mouse is not inducible and does not capture all dendritic cells. We will use an inducible CX3CR1Cre mouse to investigate the complex spectrum of dendritic cells in more detail. Moreover, we will study whether interventional knockdown also lowers blood pressure and end organ damage. Additionally, by backcrossing the knockout mouse in RAG1 deficient mice (which do not have T cells), we will investigate whether the effect is mediated by interaction with T cells. Using an infection model with a known T cell antigen, we will examine whether binding of aldosterone to the mineralocorticoid receptor in dendritic cells is the third signal in T cell activation and whether deficiency of the receptor in dendritic cells increases susceptibility to infections.To better understand the role of the mineralocorticoid receptor in dendritic cells, we will examine the cellular and secretory proteome of isolated dendritic cells with and without the receptor. To expand our knowledge about the role of the mineralocorticoid receptor in dendritic cells in humans, we have begun to investigate the receptor in dendritic cells in the kidney in accessible single cell RNAseq databases. To refine and enrich dendritic cells, we will also examine the receptor in these cells in single cell RNAseq data from CD45+ cells isolated from blood and kidney tissue from male and female patients. In addition, we will collect RNAseq data from single nuclei from patients with hypertensive nephropathy and create an inflammatory cell-epithelial cell interactome to identify new signaling pathways. We expect to get a much better understanding of the role of the complement system and the mineralocorticoid receptor in the pathogenesis of arterial hypertension and hypertensive nephropathy. The studies will be carried out in preclinical mouse models and in human kidney tissue. It is the aim to discover new pharmacologic targets for patients with arterial hypertension and hypertensive nephropathy.

• DFG Programme: Research Grants