Prof. Dr. rer. nat. Charlotte Wagner
- Important information: Institut für Physiologie - Lehrstuhl Physiologie I
Functional significance of intracellular signaling pathways in resident interstitial cells of the kidney for the development and progression of renal fibrosis
The development of chronic renal failure is a significant medical and socioeconomic problem and remains a scientific challenge despite many years of research in this field. Although the aetiology leading to chronic kidney failure is diverse, it usually results in a common final pathway in which renal functional tissue is replaced by connective tissue, leading to progressive and pathognomonic renal fibrosis. Cell types that contribute to renal fibrosis and chemical mediators that can induce or accelerate renal fibrosis are already known. Nevertheless, no effective therapy has yet been developed to prevent or reverse renal fibrosis in humans due to the cellular and multifactorial complexity of fibrosis development.
The tubulointerstitium of the normal kidney comprises different cell types, such as capillary endothelium, capillary pericytes, fibroblasts, dendritic cells and macrophages. A subpopulation of these interstitial cells stands out due to the strong expression of the PDGF-ß receptor (ß receptor for platelet derived growth factor), whereby these PDGFR-ß positive cells are most likely fibroblasts to which clear physiological and pathophysiological functions can be assigned. Pathophysiologically, the property of these cells is to transform into myofibroblasts in the event of kidney damage and thus contribute significantly to tubulointerstitial fibrosis. The intracellular signalling pathways whose activation can accelerate or slow down the transformation of PDGFR-ß positive cells into myofibroblasts have so far been insufficiently characterised.
We are now investigating the significance of classical signaling pathways, the existence of which has been proven for interstitial PDGFR-ß positive cells on the one hand, and for which there is more general evidence that they could influence renal fibrosis on the other. To this end, certain factors of the individual signaling pathways are deleted in the mouse model and the significance of these factors for the basic functions in the kidney and also for the development of fibrosis is examined in two different models for experimental tubulointerstitial fibrosis, unilateral ureteral obstruction and adenine-induced nephropathy.
Role of NFAT5 signalling in PDGFR-ß positive cells: conditional deletion of the osmosensitive transcription factor NFAT5 (nuclear factor of activated T-cells) in PDGFR-ß positive cells to investigate the role of NFAT5 in the healthy and fibrotic kidney.
Role of P2X7 in PDGFR-ß positive cells: Investigation of the importance of the purinergic signalling pathway activated by the surface receptor P2X7 in the global knockout model in the healthy and in the fibrotic kidney.
Significance of intercellular communication in PDGFR-ß positive cells via Cx43 and Panx-1: Conditional deletion of Cx43 (connexin 43) in PDGFR-ß positive cells and global deletion of Panx-1 (pannexin -1) to investigate their significance in the healthy and fibrotic kidney.