Analysis of nephroprotective effects of Fibrinogen Bß15-42

• Applicant: Dr. Inga Sörensen-Zender
• Subject Area: Nephrology
• Term: from 2013 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 237780608

The clotting protein fibrinogen plays an important role in acute and chronic disease processes that goes far beyond its traditional function as a haemostatic factor. Some degradation products of fibrinogen are of particular biological importance such as the 27 amino acid peptide Bß15-42 which is produced during plasmin-dependent fibrinolysis. In 2005 it was first shown that Bß15-42 has a potent protective effect in myocardial ischemia/reperfusion (I/R) when it is administered during the post-ischemic reperfusion phase. A competitive displacement of pro-inflammatory E1 fragments from endothelial VE-cadherin was regarded as the most likely mechanism underlying the protective effect. In addition, the binding of Bß15-42 to VE-cadherin has been shown to stimulate an endothelial signaling cascade through which a protective stabilization of the endothelial cytoskeleton is initiated. In analogy to myocardial I/R studies our preliminary work has shown, that the administration of Bß15-42 in renal I/R injury has a significant protective character on post-ischemic renal damage. In transient renal I/R, as well as in murine kidney transplantation we observed a significant reduction in renal inflammation and endothelial activation. In parallel we found significantly weaker tubular cell damage and reduced levels of epithelial apoptosis. Based on these findings, we tested the hypothesis that Bß15-42 could have a direct protective effect on renal tubular epithelial cells. Indeed, we observed, that treatment with Bß15-42 resulted in a significant improvement in cellular stress resistance of renal tubular epithelial cells in vitro. These findings suggested a previously unknown direct effect of Bß15-42 on non-endothelial epithelial cells and implied the existence of a VE-cadherin-independent mechanism of action of Bß15-42. After stimulation with Bß15-42 we observed a significant Erk activation in renal epithelial cells, which appeared mechanistically relevant since the anti-apoptotic effect of Bß15-42 decreased after Erk inhibition. An important goal of this proposal is to identify Bß15-42 interaction partners on renal epithelial cells, and to characterize the signaling pathway upstream of Erk (specific aim I). In addition, the biological relevance of the newly described mechanism will be tested and mechanistically analyzed by a series of in vivo studies (specific aim II). Finally, we will investigate the potential antagonistic effect of Bß15-42 on renal tubulointerstitial fibrosis, because our preliminary work suggests a significant impact of Bß15-42 on epithelial differentiation processes and on pro-fibrotic cell cycle behavior (specific aim III). Taken together, the present project aims at increasing our understanding of Bß15-42-mediated renal protection, which is relevant not only from a cell-biological point of view, but has practical significance against the background of future clinical studies.

• DFG Programme: Research Grants
• International Connection: Austria, Switzerland
• Participating Institution: Medizinische Universität Wien ; Universitätsklinik für Dermatologie ; Abteilung Skin & Endothelium Research Division (SERD) ; Anna Spiegel Forschungshaus; Eidgenössische Technische Hochschule Zürich (ETHZ) ; Institute of Molecular Systems Biology
• Participating Persons: Professor Dr. Peter Petzelbauer; Professor Dr. Andreas Pich; Professor Dr. Roland Schmitt; Dr. Bernd Wollscheid