Mechanisms of chronic kidney disease (CKD) induced by JAK2-mutated hematopoiesis

• Applicants: Professor Dr. Florian Heidel; Dr. Florian Siegerist
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566825502

Myeloproliferative neoplasms (MPNs) are hematologic malignancies frequently driven by JAK2-V617F mutations, leading to chronic inflammation and cytokine dysregulation. Up to 29% of MPN patients develop chronic kidney disease (CKD), significantly exceeding the prevalence in the general population. Despite this association, the underlying mechanisms linking JAK2-mutated hematopoiesis and kidney dysfunction remain poorly understood. In our preliminary experiments, we found mesangial cell (MC) injury as a cause for CKD in animal models and kidney biopsies. This project aims to elucidate the pathophysiology of CKD in JAK2-mutated MPN by investigating MC injury and inflammation-driven glomerular remodeling. Using a combination of transgenic Jak2V617F mouse models and human kidney biopsies, we will analyze mesangial alterations, extracellular matrix deposition, and inflammatory signaling pathways at single-cell resolution. Spatial proteomic and transcriptomic analyses will provide insights into cell-type-specific responses and crosstalk between hematopoietic and renal cells. We will employ scRNA-seq and bulk proteomics of isolated glomeruli to identify transcriptional and protein-level changes in MCs. Additionally, murine chimeric models will allow us to track long-term JAK2-mutant clonal hematopoiesis and its impact on kidney function. Pharmacologic JAK inhibition will be tested to assess its potential to reverse CKD-related glomerular damage. To complement these findings, we will perform spatial proteomic analysis of thrombogenic markers in kidney tissue to explore local procoagulant environments. Furthermore, CRISPR-based functional screens in primary MCs will identify key molecular targets contributing to mesangial injury. This interdisciplinary approach will provide novel mechanistic insights into JAK2-driven CKD and identify potential therapeutic targets. By integrating cutting-edge molecular techniques with in vivo disease models, our findings could pave the way for personalized treatment strategies aimed at preventing or mitigating kidney dysfunction in MPN patients.

• DFG Programme: Research Grants
• Co-Investigators: Professorin Dr. Nicole Endlich, Ph.D.; Privatdozentin Dr. Tina Schnöder