Interaction of monocytes with glomerular mesangial cell matrix in the pathogenesis of glomerular injury.
Doctoral thesis, UCL (University College London).
Acute inflammatory kidney diseases may resolve, leaving limited residual damage or progress to cause chronic renal scarring characterized by glomerulosclerosis and interstitial fibrosis. Understanding the mechanisms that control inflammation within the kidney may facilitate the development of treatment strategies to prevent irreversible kidney damage and slow progression of chronic kidney disease. Infiltration of mononuclear cells is recognized as an early event in many different conditions that may ultimately lead to kidney injury. Having extravasated from blood vessels at sites of injury, these multifunctional cells differentiate into tissue macrophages, which depending on their phenotype, have the potential to both promote resolution of inflammation or to cause scarring, making them an attractive target for therapy. Having left the glomerular capillary lumen, mononuclear cells are very likely to encounter the mesangial matrix. It was therefore hypothesized that interactions between monocytes and matrix components might modify the behavior of the infiltrating cells and thereby modify the outcome of the inflammatory process. The work presented in this thesis demonstrates that mesangial matrix activates monocytes leading to expression of peroxisome proliferators activated receptor γ and the CD36 scavenger receptor, both markers of macrophage differentiation. Since LDL accumulation in the mesangium may contribute to glomerular injury, the interaction between this lipoprotein and the matrix was also examined. These studies demonstrated that LDL becomes oxidized when exposed to matrix components, possibly due to loss of protective antioxidants. The presence of oxidized LDL has the potential to induce mesangial cell chemokine production, which is likely to promote further monocyte influx into the glomerulus. Furthermore, matrix-activated monocytes internalized oxidized LDL via CD36 scavenger receptor, leading to foam cell formation, a recognized characteristic feature of glomerular injury. Foam cell formation may in turn amplify and perpetuate the disease process by driving further production of cytokines and growth factors. Finally, to establish that these observations were relevant to human glomerular disease, the presence of macrophages expressing PPAR-γ and the CD36 scavenger receptor in human kidney biopsy samples taken from patients with inflammatory glomerular disease was demonstrated, using sections from non-inflamed kidneys as controls. These observations imply that monocyte-matrix interactions are important in the context of glomerular disease and may represent a potential target for therapies designed to limit injury resulting from glomerular inflammation.
|Title:||Interaction of monocytes with glomerular mesangial cell matrix in the pathogenesis of glomerular injury|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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