Mechanisms and consequences of TGF-ß overexpression by podocytes in progressive podocyte disease

In patients with progressive podocyte disease, such as focal segmental glomerulosclerosis (FSGS) and membranous nephropathy, upregulation of transforming growth factor-ß (TGF-ß) is observed in podocytes. Mechanical pressure or biomechanical strain in podocytopathies may cause overexpression of TGF-ß and angiotensin II (Ang II). Oxidative stress induced by Ang II may activate the latent TGF-ß, which then activates Smads and Ras/extracellular signal-regulated kinase (ERK) signaling pathways in podocytes. Enhanced TGF-ß activity in podocytes may lead to thickening of the glomerular basement membrane (GBM) by overproduction of GBM proteins and impaired GBM degradation in podocyte disease. It may also lead to podocyte apoptosis and detachment from the GBM, and epithelial-mesenchymal transition (EMT) of podocytes, initiating the development of glomerulosclerosis. Furthermore, activated TGF-ß/Smad signaling by podocytes may induce connective tissue growth factor and vascular endothelial growth factor overexpression, which could act as a paracrine effector mechanism on mesangial cells to stimulate mesangial matrix synthesis. In proliferative podocytopathies, such as cellular or collapsing FSGS, TGF-ß-induced ERK activation may play a role in podocyte proliferation, possibly via TGF-ß-induced EMT of podocytes. Collectively, these data bring new mechanistic insights into our understanding of the TGF-ß overexpression by podocytes in progressive podocyte disease

Non-local damage-enhanced MFH for multiscale simulations of composites

In this work, a gradient-enhanced mean-field homogenization (MFH) procedure is proposed for fiber reinforced materials. In this approach, the fibers are assumed to remain linear elastic while the matrix material obeys an elasto-plastic behavior enhanced by a damage model. As classical finite element simulations face the problems of losing uniqueness and strain localization when strain softening of materials is involved, we develop the mean-field homogenization in a non-local way. Toward this end we use the so-called non-local implicit approach, reformulated in an anisotropic way to describe the damage in the matrix. As a result we have a multi-scale model that can be used to study the damage process at the meso-scale, and in particular the damaging of plies in a composite stack, in an efficient computational way. As a demonstration a stack with a hole is studied and it is shown that the model predicts the damaging process in bands oriented with the fiber directions.SIMUCOMP no 1017232 (CT-EUC 2010-10-12