Therapeutic strategies and molecular mediators of renal pathology in cardiorenal syndrome type 2

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Cardiac and renal dysfunction frequently coexist and form a pathophysiological cycle with an adverse impact on short- and long-term morbidity and mortality. The clinical entity cardiorenal syndrome (CRS) describes the combined dysfunction of the heart and the kidney. CRS type 2 is characterized by chronic heart failure causing progressive chronic kidney disease (CKD) and recognized as the most frequent subtype of CRS. Worsening kidney function in the context of heart failure significantly increases adverse outcomes, but therapeutic options to slow progression of CKD and prevent end-stage renal disease are limited and in need for expansion. While the impact of hemodynamic parameters such as hypoperfusion and renal congestion are discussed as driving forces for the development of CKD in CRS type 2, little is known about the non-hemodynamic pathways relevant for the onset and progression of CKD in CRS type 2. This project aims to establish the role of extracellular vesicle (EV) dependent interorgan communication by microRNA (miRNA) transfer from cardiac to renal cells as a non-hemodynamic factor relevant for the renal pathology in CRS type 2 and to explore its therapeutic implications. The underlying hypothesis for this project is that cardiomyocytes under conditions of chronic heart failure secrete EVs containing miRNAs that target renal fibroblasts and pericytes which induce myofibroblast transdifferentiation and promote renal fibrogenesis. The following aims are set to address this hypothesis: (Aim 1) angiotensin II treated cardiomyocyte derived EVs as wells as serum derived EVs from mice suffering chronic heart failure are characterized and analyzed for the capacity of myofibroblast transdifferentiation of renal target cells (fibroblasts and pericytes) in vitro and in vivo. Cell culture derived fluorescently labeled EVs detected by in vivo imaging system (IVIS) and transgenic inducible green fluorescent protein (GFP) EV reporter mouse strains will be used to identify renal target cells in vivo. (Aim 2) The transverse aortic constriction (TAC) model mimicking CRS type 2 will be used to identify candidate EV miRNAs (small RNA sequencing) that precede or accompany pathologic changes in renal function, structure and composition in response to heart insufficiency. (Aim 3) In addition, preexisting compounds such as lycorine, that has been recently identified by Thomas Thums´ group, will be tested for its therapeutic potential in primary renal disease as well as CRS type 2 due to its antifibrotic capacity.