Popis: |
Podocyte damage is the primary cause of chronic renal insufficiency, which can lead to focal segmental glomerulosclerosis (FSGS). From a certain threshold this loss leads to a terminal loss of renal function. Podocytes are the "Achilles heel" in this loop because they are so called post-mitotic cells. Parietal epithelial cells (PECs) proliferate life long, are located next to podocytes, and are expressing classical stem cell marker proteins. For this reason, parietal epithelial cells present a potential adult progenitor cell population. Within this thesis we discovered a regenerative mechanism in the glomerulus of the kidney, in the sense of a transdifferentiation of parietal epithelial cells into podocytes. For this purpose, a closer characterization of transient cells has been performed and we validated our triple transgenic pPEC / LC1 / R26R mouse model. Using this triple transgenic mouse line, we were able to genetically label parietal epithelial cells at any time. Furthermore, extensive cell lineage experiments were performed within newborn, adult and nephrectomized pPEC / LC1 / R26R mice. Characterization of the transient cells showed that these cells exhibit an intermediate phenotype between parietal epithelial cells and podocytes. These data supported our hypothesis that transient cells are parietal cells transdifferenting into podocytes. Within this thesis the pPEC / LC1 / R26R mouse model was characterized in terms of its usefulness for cell lineage experiments. A specific, reproducible labeling of the parietal epithelial cells could be induced and demonstrated the suitability of the animal model for the necessary cell lineage experiments. In our cell lineage experiments, the above-mentioned genetic labeling was used to reveal the transdifferentiation of parietal epithelial cells into podocytes. It was possible to induce the specific transgene expression in newborn animals and to detect podocyte recruitment from parietal epithelial cells. We have not been able to detect such transdifferentiation in adult and nephrectomized (uni-nephrectomy and 5/6 nephrectomies) mice. One of the next steps on the way into a potential clinical application must be the detection of a podocyte regeneration in adult animals and the proof of a controllability of this regenerative mechanism. |