Therapeutic strategies and molecular mediators of renal pathology in cardiorenal syndrome type 2
Final Report Abstract
The combined occurrence of heart and kidney failure, also known as cardiorenal syndrome, is of high clinical relevance due to its frequency and increased mortality. In this project, the animal model of transverse aortic constriction (TAC) was used to simulate the development of cardiorenal syndrome. In addition to known pathomechanisms such as activation of the renin-angiotensin-aldosterone system (RAAS), transcriptional analyses identified potentially relevant genes and signaling pathways in the early stages of renal injury. Histopathologically, organ fibrosis is found in both the heart and kidney in cardiorenal syndrome. Two substances, Lycorine and its derivative Homoharringtonine, already showed antifibrotic potential in the development of cardiac fibrosis. In this project it was shown that both substances inhibit the proliferation and migration of renal fibroblasts as well as their activation to myofibroblasts and thereby prevent the excessive production of extracellular matrix in vitro. In addition, both substances attenuated the increased contractility and metabolic switch to aerobic glycolysis observed upon activation to myofibroblasts. Also in the ex vivo model of the Precision-Cut-Kidney-Slices, a reduction in expression of genes coding for components of the extracellular matrix could be observed, especially for Homoharringtonine. The data collected suggest that the antifibrotic efficacy of both substances is due to an interaction with the TGFβ signaling pathway, which is known to be a key regulator in fibrosis. Both substances are therefore a possible strategy for preventing the organ fibrosis of both heart and kidney in cardiorenal syndrome, where Homoharringtonine is more effective than Lycorine.
