DFG Research Group 406
Speaker: Prof. Dr. W. Kriz
|
DFG Research Group 406 Speaker: Prof. Dr. W. Kriz |
|
|
| |
| Home > | |
|
The progression of chronic renal disease tends to follow a stereotypical course in many cases . Regardless of the nature of the initial insult, once a substantial portion of the renal tissue has been destroyed, there is a steady decline in renal function with time associated with the progressive loss of viable nephrons. A common histologic finding in these cases is focal segmental glomerulosclerosis (FSGS) with tubulointerstitial fibrosis. Somewhat simplified there are three different hypotheses about the mechanisms which account for the loss of nephrons in FSGS. First, a inordinated and exuberant proliferation of mesangial cells together with an overproduction of extracellular matrix have been suggested to lead to a progressive obliteration of glomerular capillaries and thereby to glomerulosclerosis. Second, an initial glomerular damage may encroach into the tubular interstitium and develop into a self perpetuating process with proliferation and matrix deposition, which leads to the degeneration of nephrons. Third, the podocyte hypothesis postulates that the inability of podocytes to undergo regenerative cell replication is the decisive factor underlying disease progression. The podocyte hypothesis is favored in Heidelberg for the following reasons: There is strong evidence that the podocyte is incapable of regenerative replication postnatally; when podocytes are lost they cannot be replaced by new cells. Loss of podocytes may therefore produce areas of bare glomerular basement membrane (GBM), which represent potential starting points for irreversible glomerular injury. Attachment of parietal cells to the GBM leads to the formation of a tuft adhesion to Bowman's capsule, the first "committed" lesion to develop into segmental sclerosis. Within an adhesion the tuft merges with the interstitium allowing filtration from perfused capillaries inside the adhesion towards the interstitium. In response, interstitial fibroblasts establish a barrier that prevents the dissipation of the filtrate into the surrounding interstitium. Instead the spreading of the filtrate is restricted to the outer surface of the affected nephron. This results in the progression of the segmental glomerular injury to global sclerosis, and via the urinary pole to tubular degeneration. Glomerulus and tubule are finally replaced by fibrous tissue. This pathway assures that the destructive effects remain confined to the initially affected nephrons. There is no nephron-to-nephron transfer at the level of the tubulointerstitium. This concept includes that the progressive loss of nephrons always starts separately in each nephron in the glomerulus with the loss of podocytes. In addition to the original factors that led to the initial injury of podocytes, the two most important additional factors weakening the podocyte in the progressive phase of renal failure are glomerular hypertension and increased protein leakage through the GBM. The various projects of our group pursue different aspects associated with this hypothesis. They deal with the relevance of two transcription factors (WT1, LMX1B) for the proper development and maintenance of the glomerular filter, the role of AT1 and AT2 receptors on podocytes as targets for cytoskeletal changes and proteinuria treatment, the relevance of reactive oxygen species in glomerular diseases and in transplant survival, and the role of podocytes in disease progression in mesangio-proliferative as well as crescentic glomerulonephritis. | |
| Members of the Research Group | |
| Research Topics: An Overview |
|
| |||
| Responsible: Prof. Dr. W. Kriz | Page edition | ||
