Role of the anaphylatoxin receptors in glomerulonephritis in human and mice

• Applicant: Dr. Leonie Dreher
• Subject Area: Nephrology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564421383

The complement system, as a central component of innate immunity, not only protects against pathogens, but also plays a key role in the acquired immune system, cell metabolism and tissue homeostasis. The anaphylatoxins C3a, C5a and their receptors C3aR, C5aR1 and C5aR2 are central to these functions. The growing repertoire of new therapeutics in the field of the complement system has significantly increased scientific and clinical interest, especially in kidney diseases. This project aims to investigate the role of anaphylatoxins and their receptors in nephritic and nephrotic glomerulonephritis in order to develop new, personalized treatment options. The C5aR1 inhibitor avacopan was recently approved for ANCA-associated vasculitis (AAV). However, the underlying molecular mechanisms and the potentially synergistic effects of a combined blockade of several complement receptors are still poorly understood. We will investigate the localization and expression of anaphylatoxin receptors in human kidney biopsies using single-cell analyses, immunohistochemistry and RNAScope. Initial data show an upregulation of transcription and translation of C3aR and C5aR1 in kidney biopsies from AAV patients. Additionally, the additive effect of a combined C3aR/C5aR1 and C5aR1/C5aR2 deficiency will be analyzed in the mouse model of nephrotoxic nephritis. Preliminary work shows that double deficiency of C3aR/C5aR1 reduces glomerular damage, lowers albuminuria and shifts the balance between pro-inflammatory Th17 cells and anti-inflammatory regulatory T cells (Tregs) in favor of Tregs. There is also clear evidence of involvement of the complement system in membranous glomerulonephritis, the most common form of nephrotic glomerulonephritis in adults. Our hypothesis is that the receptors C3aR and C5aR1 contribute to the pathogenesis and that their inhibition has a protective effect. We will analyze the localization and expression of the receptors in human tissue and investigate the influence of knockouts on the development and progression of the disease in the active THSD7A mouse model. This will clarify whether protective effects are mediated by receptors on infiltrating or resident kidney cells. Initial results show reduced albuminuria in C3aR knockout mice. The aim of the project is to gain a deeper understanding of the role of the complement system in the pathophysiology of glomerulonephritis and to identify new pharmacological target structures through studies in human kidney tissue and preclinical mouse models.

• DFG Programme: Research Grants