The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A.
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 beta 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.
Faul
Christian
C
Department of Medicine, University of Miami Miller School of Medicine, 1600 Northwest Tenth Avenue, Miami, Florida 33136, USA.
Donnelly
Mary
M
Merscher-Gomez
Sandra
S
Chang
Yoon Hee
YH
Franz
Stefan
S
Delfgaauw
Jacqueline
J
Chang
Jer-Ming
JM
Choi
Hoon Young
HY
Campbell
Kirk N
KN
Kim
Kwanghee
K
Reiser
Jochen
J
Mundel
Peter
P
D048948:14-3-3 Proteins / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D003599:Cytoskeleton / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*
D048948:14-3-3 Proteins; D000199:Actins; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D008840:Microfilament Proteins; C503968:Synpo protein, mouse; D016572:Cyclosporine