Role of the matrikine CCN1 in the context of chronic renal injury – implications of aberrant tubular-interstitial crosstalk and autocrine signaling

• Applicant: Professor Dr. Christoph B. Schell
• Subject Area: Nephrology ; Pathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562400794

Chronic kidney disease (CKD) is characterized by an increasing incidence worldwide. The main histological changes in renal tissue are interstitial fibrosis and tubular atrophy, which is characterized by a thickening of the tubular basement membrane. Based on in vitro and in situ preliminary data, we were able to show that tubular atrophy is associated with an increased expression of cell-matrix receptors in renal tubular epithelia. This intensified interaction between cells and surrounding substrate translates in an altered secretory repertoire of tubule cells. Based on this, further studies led to the identification of the matrikine CCN1 in renal injury models of mice as well as in human kidney biopsy samples from CKD patients. Furthermore, we were able to show that CCN1 induces senescence mechanisms in renal epithelial cells and has a chemoattractive and activating effect on macrophages. In the proposed research project, we want to build on these observations by using new in vivo models (cell-specific knockout, knock-in models) to elucidate the functional relevance of CCN1 for the pathogenesis of CKD. Furthermore, mechanistic studies will characterize which mechanisms lead to the induction of CCN1, how this protein is post-translationally modified by proteolytic processing and which signaling cascades are finally triggered. Finally, a complementary approach of spatial transcriptomics and proteomics on human kidney biopsy samples will be used to investigate the complex interaction of CCN1 (and other matrikines) and parameters such as inflammatory cells, fibroblasts and extracellular matrix components. Overall, this research project should contribute to a comprehensive understanding of the complex and context-dependent functions of the matrikine protein CCN1 in the pathogenesis of chronic kidney disease. The results may lay the basis for the development of innovative diagnostic and potentially also therapeutic approaches that target CCN1-regulated signaling pathways.

• DFG Programme: Research Grants