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

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized bymutations in <em>PKD1</em> or <em>PKD2</em>, 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 (<em>Pkd1</em>^RC/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 <em>Pkd1</em>^RC/RC mice, isolated at a stage before cysts were observed, already showed enhanced cystogenesis <em>in vitro</em>. These findings underscore the crucial role of tissue-resident macrophages in ADPKD and suggest targeting epithelial cell–macrophage interactions as a promising therapeutic avenue.