The chemokine (C-C motif) ligand protein synthesis inhibitor bindarit prevents cytoskeletal rearrangement and contraction of human mesangial cells

Intraglomerular mesangial cells (MCs) maintain structural and functional integrity of renal glomerular microcirculation and homeostasis of mesangial matrix. Following different types of injury, MCs change their phenotype upregulating the expression of alpha-smooth muscle actin (alpha-SMA), changing contractile abilities and increasing the production of matrix proteins, chemokines and cytokines. CCL2 is a chemokine known to be involved in the pathogenesis of renal diseases. Its glomerular upregulation correlates with the extent of renal damage. Bindarit is an indazolic derivative endowed with anti-inflammatory activity when tested in experimental diseases. It selectively inhibits the synthesis of inflammatory C-C chemokines including CCL2, CCL7 and CCL8. This work aims to analyse bindarit effects on ET1-, AngII- and TGF beta-induced mesangial cell dysfunction. Bindarit significantly reduced Angll-, ET1- and TGF beta-induced alpha-SMA upregulation. In a collagen contraction assay, bindarit reduced AngII-, ET1- and TGF beta-induced HRMC contraction. Within 3-6 h stimulation, vinculin organization and phosphorylation was significantly impaired by bindarit in AngII-, ET1- and TGF beta-stimulated cells without any effect on F-actin distribution. Conversely, p38 phosphorylation was not significantly inhibited by bindarit. Our data strengthen the importance of CCL2 on ET-1, AngII- and TGF beta-induced mesangial cell dysfunction, adding new insights into the cellular mechanisms responsible of bindarit protective effects in human MC dysfunction. (C) 2016 Elsevier Ltd. All rights reserved.