The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A

Christian H Faul, Mary Donnelly, Sandra M Merscher-gomez, Yoon Hee Chang, Stefan Franz, Jacqueline Delfgaauw, Jer Ming Chang, Hoon Young Choi, Kirk N. Campbell, Kwanghee Kim, Jochen Reiser, Peter Mundel

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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-14-3-3β 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.

Original languageEnglish
Pages (from-to)931-938
Number of pages8
JournalNature Medicine
Volume14
Issue number9
DOIs
StatePublished - Sep 1 2008

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Faul, C. H., Donnelly, M., Merscher-gomez, S. M., Chang, Y. H., Franz, S., Delfgaauw, J., Chang, J. M., Choi, H. Y., Campbell, K. N., Kim, K., Reiser, J., & Mundel, P. (2008). The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nature Medicine, 14(9), 931-938. https://doi.org/10.1038/nm.1857