Cytoskeletal Reorganization by Mycophenolic Acid Alters Mesangial Cell Migration and Contractility

Abstract

Abstract-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 mol/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 ␣-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.

Effects of Mycophenolic Acid on Human Fibroblast Proliferation, Migration and Adhesion In Vitro and In Vivo

“…In renal transplant recipients, the relative risk for wound infections was found to be 2.43 and for hernia or fascial dehiscence to be 3.54 in the presence of MPA as compared to azathioprine. MPA was found to be a stronger risk factor for wound infection than diabetes and to be the second most significant risk factor for an incisional hernia or fascial dehiscence (20) (17,18 …”

Mycophenolic acid in Rheumatology: mechanisms of action and severe adverse events

“…MPA (1-10 µM) inhibits proliferation and extracellular matrix (ECM: type I collagen and fibronectin) production in human mesangial cells, and their contraction and migration skills in vitro (41). Recently, MPA was found to inhibit anti-DNA antibody-induced PKC activation and subsequent TGFβ and fibronectin synthesis in human mesangial cells, and reduced proteinuria in lupus-prone mice (42).…”

Two-dimensional gel electrophoresis maps of the proteome and phosphoproteome of primitively cultured rat mesangial cells

“…MC play an important role in maintaining the structure and function of the glomerulus including the production of growth factors to allow normal cell turnover [1], provision of structural support for the capillaries via the production of mesangial matrix [2], modulation of glomerular hemodynamics via their contractile properties [3], and phagocytic function allowing removal of macromolecules and immune complexes [4]. The proliferation of MC is a prominent feature of glomerular disease including immunoglobulin A (IgA) nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy [5].…”