Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent

Hemodynamic abnormalities are important in the pathogenesis of the excess m esangial matrix deposition of diabetic and other glomerulopathies. p38-Mito gen-activated protein (MAP) kinase, an important intracellular signaling mo lecule, is activated in the glomeruli of diabetic rats. We studied, in huma n mesangial cells, the effect of stretch on p38 MAP kinase activation and t he role of p38 MAP kinase in stretch-induced fibronectin and transforming g rowth factor-beta 1 (TGF-beta 1) accumulation. p38 MAP kinase was activated by stretch in a rapid (11-fold increase at 30 min, P < 0.001) and sustaine d manner (3-fold increase at 33 h, P < 0.001); this activation was mediated by protein kinase C (PKC). Stretch-induced fibronectin and TGF-beta 1 prot ein levels were completely abolished (100% inhibition, P < 0.001; and 92% i nhibition, P < 0.01, respectively) by SB203580, a specific p38 MAP kinase i nhibitor. At 33 h, TGF-beta 1 blockade did not affect stretch-induced fibro nectin production, but partially prevented stretch-induced p38 MAP kinase a ctivation (59% inhibition, P < 0.05). TGF-beta 1 induced fibronectin accumu lation after 72 h of exposure via a p38 MAP kinase-dependent mechanism (30% increase over control, P < 0.01). In human mesangial cells, stretch activa tes, via a PKC-dependent mechanism, p38 MAP kinase, which independently ind uces TGF-beta 1 and fibronectin. In turn, TGF-beta 1 contributes to maintai ning late p38 MAP kinase activation, which perpetuates fibronectin accumula tion.