Cytoskeletal reorganization by mycophenolic acid alters mesangial cell migration and contractility.
Cytoskeleton alterations are a hallmark of mesangial cell activation during glomerulosclerosis. The aim of this study was to investigate whether mycophenolic acid (MPA) affects cytoskeletal organization and motility of human mesangial cells. Using the IP15 cell line, we found that treatment with 1 micromol/L MPA inhibited both receptor-dependent (angiotensin II) and receptor-independent (KCl) contractile responses, as well as serum-induced migration activity, suggesting alterations in the intracellular mechanisms that control mesangial cell motility. Immunofluorescence studies of MPA-treated cells provided evidence for decreased membrane disassembly/reassembly of alpha-smooth muscle actin and F-actin fibers, which was correlated with sustained quantitative and qualitative modifications of actin-associated proteins: calponin was overexpressed and became associated with actin fibers, whereas phosphorylation levels of cofilin and myosin light chain increased, suggesting both an activation of the mechanisms responsible for actin polymerization and an inhibition of actin-depolymerizing processes. These observations support a stabilizing effect of MPA on the mesangial actin cytoskeleton, which constitutes an additive action by which MPA, beyond its anti-inflammatory, antiproliferative and antifibrotic properties, might protect against excessive mesangial activation in the context of various glomerulopathies and kidney transplantation.
Dubus
Isabelle
I
Unité INSERM 441, Bordeaux, France. dubus@biophar.u-bordeaux2.fr
L'Azou
Beatrice
B
Gordien
Myriam
M
Delmas
Yahsou
Y
Labouyrie
Jean-Pierre
JP
Bonnet
Jacques
J
Combe
Christian
C
D000804:Angiotensin II / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000648:ultrastructure; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009173:Mycophenolic Acid / Q000494:pharmacology*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects
D003598:Cytoskeletal Proteins; D007166:Immunosuppressive Agents; D018994:Myosin Light Chains; D000804:Angiotensin II; D009173:Mycophenolic Acid