how does rituximab functions in altering the activity level of the so-called "permeability factor." Definitely an area for research, I was unable to find more than hypothesis. What I came across, however, was this article published in NEJM just over a year ago. The author was struck by the work of researchers who discovered that the influence of calcineurin inhibitors on proteinuric kidney disease goes beyond the inhibition of T lymphocyte signaling by IL-1, which is obviously key in the development of inflammatory disease states that increase glomerular capillary permeability. This action does not necessarily explain calcineurin inhibitors' advantageous role in non-inflammatory conditions including minimal change disease and focal glomerular sclerosis.
The podocyte structure may hold the answer. Synaptopodin stabilizes the actin cytoskeleton of the podocyte and is protected from degradation by phosphorylation. Calcineurin dephosphorylates synaptopdin, subjecting it to degradation by cathepsin L and essentially losing its stabilizing properties. Faul et al showed that the inhibition of calcineurin by cyclosporine A protected against lipopolysaccaride-induced proteinuria in mice, and also demonstrated that activation of calcineurin in the podocyte is sufficient to cause proteinuria by causing degradation of synaptopodin.
This research provides a foundation for new ideas regarding the activity of "immunosuppression" in the treatment of proteinuric disease and novel areas for pharmacologic development.
Friday, February 12, 2010
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