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Article
Nature Medicine 14, 931 - 938 (2008)
Published online: 24 August 2008 | doi:10.1038/nm.1857
The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A
Christian Faul1,2, Mary Donnelly1,2, Sandra Merscher-Gomez1,2, Yoon Hee Chang2,5, Stefan Franz2,5, Jacqueline Delfgaauw2,5, Jer-Ming Chang3, Hoon Young Choi2, Kirk N Campbell1,2, Kwanghee Kim2, Jochen Reiser1,4 & Peter Mundel1,2
Abstract
The immunosuppressive action of the calcineurin inhibitor cyclosporine A (CsA) stems from the inhibition of nuclear factor of activated T cells (NFAT) signaling in T cells. CsA is also used for the treatment of proteinuric kidney diseases. As it stands, the antiproteinuric effect of CsA is attributed to its immunosuppressive action. Here we show that the beneficial effect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from the stabilization of the actin cytoskeleton in kidney podocytes. CsA blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin–14-3-3
interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L–mediated degradation. These results represent a new view of calcineurin signaling and shed further light on the treatment of proteinuric kidney diseases. Novel calcineurin substrates such as synaptopodin may provide promising starting points for antiproteinuric drugs that avoid the serious side effects of long-term CsA treatment.
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