Mesangial cells and glomerular inflammation: from the pathogenesis to novel therapeutic approaches

Abstract

The mesangium occupies a central anatomical position in the glomerulus, and also plays an important regulatory role in immune-mediated glomerular diseases, with an active participation in the response to local inflammation. In general, the mesangial cell responses to the pathological stimuli are associated with the main events of glomerular injury: leukocyte infiltration, cell proliferation and fibrosis. Leukocyte migration and infiltration into the glomerulus is responsible for the initiation and amplification of glomerular injury, and is mediated by adhesion molecules and chemokines, which can be locally synthesized by mesangial cells. The increase in mesangial cell number is also due to proliferation of intrinsic mesangial cell population. Regulatory mechanisms of mesangial cell replication include a complex array of factors which control cell proliferation, survival and apoptosis. Mesangial matrix accumulation leading to glomerulosclerosis, is a consequence of an imbalance between matrix production and degradation, and is controlled by growth factors and pro-inflammatory cytokines. The initial phase of immune-mediated glomerular inflammation depends on the interaction of immune complexes with specific Fc receptors in infiltrating leukocytes and resident mesangial cells, the ability of immune complexes to activate complement system, and on local inflammatory processes. Activated mesangial cells then produce many inflammatory mediators leading to amplification of the injury. This review will focus on the biological functions of mesangial cells that contribute to glomerular injury, with special attention to immune-mediated glomerulonephritis. Furthermore, new therapies based on the pathophysiology of the mesangial cell that are being developed in experimental models are also proposed.