Friday, October 10, 2008

New Mechanism for Cyclosporin in Proteinuric Disease

Cyclosporin A (CsA) has been a mainstay of therapy for nephrologists: it (along with tacrolimus) has become the cornerstone of immunosuppressant therapy for kidney transplant patients; in addition, it has also seen use as an effective agent in proteinuric disease states such as membranous nephropathy, FSGS, and minimal change disease.

The mechanism by which CsA acts as an immunosuppressant is well worked out: it binds to and inhibits calcineurin, an intracellular phosphatase, and thereby prevents the transcription factor NFAT from translocating to the nucleus and upregulating IL-2 transcription.

However, new data presented in a recent Nature Medicine paper suggests an entirely new mechanism by which CsA acts in the treatment of nephrotic syndrome: it tightens up the actin cytoskeleton of the podocyte which is required for maintaining a working slit diaphragm. In this paper, the authors demonstrate that CsA blocks the calcineurin-mediated dephosphorylation of synaptopodin, a protein in podocytes which regulates the actin cytoskeleton. As mentioned recently in this blog, we know already know that the actin cytoskeleton is critical for maintaining the filtration barrier as genes such as alpha-actinin 4 when mutated result in congenital FSGS.

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