The role of renal macrophage-epithelial cell interactions in promoting polycystic kidney disease (PKD) progression

• Applicant: David Nicolas Gonilski Pacin, Ph.D.
• Subject Area: Cell Biology ; Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575236818

Autosomal-dominant polycystic kidney disease (ADPKD) is a severe genetic disorder that leads to progressive kidney cyst formation, organ enlargement, and ultimately kidney failure. Despite its prevalence, treatment options remain limited, with Tolvaptan being the only FDA-approved drug that slows down but does not stop disease progression. The molecular mechanisms that drive cystogenesis remain insufficiently understood, hindering the development of effective therapeutic strategies.This project focuses on the crosstalk between renal epithelial cells and macrophages (immune cells) in ADPKD, a crucial but not fully characterized aspect of disease progression. Recent evidence suggests that macrophages exacerbate cyst growth, yet the molecular pathways mediating this interaction remain unclear. This project aims to address two fundamental questions: 1. How do renal epithelial cells communicate with macrophages in a PKD context and change their function? 2. How do macrophages contribute to disease progression and worsen the phenotype?Elucidating the interactions between immune and renal epithelial cells in ADPKD will provide novel insights into the role of inflammation and immune modulation in cyst development, allowing us to identify new therapeutic targets by focusing on secreted signaling proteins that mediate this crosstalk.Based on these questions, the main objective is to identify and analyze the sequence of events how renal epithelial cells and macrophages communicate during PKD development. I hypothesize that the interaction is controlled by protein secretion and paracrine signaling. To test this, I will address the following objectives:Objective 1: Analyse the secretome of renal epithelial cells and identify the proteins that influence macrophage reprogramming. Objective 2: Identify how reprogrammed macrophages promote disease progression.For this I will use optogenetics, a 3D co-culture system incorporating renal epithelial cells and tissue-resident macrophages derived from a murine model which mimics a genetic variant of ADPKD in humans, RNA-seq, Flow Cytometry, and advanced proteomics. This integrative approach will bridge molecular findings with immunological mechanisms, offering a broader perspective on disease progression. By identifying how epithelial-derived signals reprogram macrophages, and how they, in turn, influence and contribute to disease progression, this research will offer novel insights into immune regulation in ADPKD.This study will be conducted at the University of Bonn, benefiting from world-leading expertise in ciliary signaling, immunology, and mass spectrometry.

• DFG Programme: WBP Position