The role of mononuclear phagocytes in the development of FSGS

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The pathogenesis of podocytopathies like focal-segmental glomerulosclerosis is complex. The immunological mechanisms involved are poorly understood and proteinuria itself is a proinflammatory stimulus. Although Mononuclear phagocytes (monocytes, dendritic cells (DCs) and macrophages) are the main constituents of the intrarenal immune system, their contribution to disease progression in podocytopathies is still unclear. In this research project, we will analyze mice which carry pathogenic NPHS2 mutations resulting in progressive proteinuria similar to FSGS. Glomeruli of these mice show a robust activation of proinflammatory pathways and periglomerular and tubulointerstitial infiltrates. First, we will analyze key immune cell subsets, focusing on mononuclear phagocytes at different stages of disease and clarify which role monocytes and dendritic cells play (Aim 1). Secondly, we will neutralize monocyte-attracting cytokines by a chemical compound and two antibodies (Aim2). We will visualize disease progression and immune cell infiltration on a whole organ level by performing light sheet fluorescence microscopy of optically cleared kidneys (Aim 3). Finally, will take advantage of the newly established MCD/FSGS-register (FOrMe) to characterize blood and urinary immune cells of patients during the first diagnosis, remission and recurrence of the disease and correlate these finding with the disease outcome. We will perform single nucleus RNAseq of urinary cells from MCD and FSGS patients to gain in-depth insight into molecular mechanisms and establish a new diagnostic tool (Aim 4). Our project will not only provide a deeper understanding of immune cell function in the pathogenesis of FSGS but will also help personalizing immunosuppressive strategies based on immune cell data, enabling clinicians to choose the optimal treatment options for each individual.