Renal tissue-resident macrophages promote cystogenesis in early polycystic kidney disease

Autosomal-dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by mutations in PKD1 or PKD2, which drive cystogenesis in renal epithelial cells. Immune cells, particularly macrophages, contribute to disease progression, yet their role remains incompletely understood. Here, we performed an in-depth analysis of renal macrophage ontogeny and phenotype and investigated their function in an ADPKD mouse model (Pkd1RC/RC) with adult onset and slow disease progression. We demonstrate that the numbers of tissue-resident macrophages were already increased before cyst formation. Using a flow cytometry screening panel, we further characterized the tissue-resident macrophage populations using surface markers and identified a novel marker that shows the potential to determine macrophage remodeling at different disease stages. To reveal the cellular interaction of tissue-resident macrophages and renal epithelial cells in further detail, we established a 3D co-culture system, demonstrating that tissue-resident macrophages from Pkd1RC/RC mice, isolated at a stage before cysts were observed, already showed enhanced cystogenesis in vitro. These findings underscore the crucial role of tissue-resident macrophages in ADPKD and suggest targeting epithelial cell-macrophage interactions as a promising therapeutic avenue.