Chronic renal failure is characterized by its progressive loss of kidney functions, without therapeutic possibilities. One of the main factors that entail chronic renal failure is glomerular hypertension, which is responsible for the loss or the damage of a highly-specialized epithelial cells of the glomerulus, the podocyte.
Podocytes covering the outer aspect of glomerular capillaries and perform interdigitations by their foot processes forming the filter barrier in kidney. The organization of the actin cytoskeleton of podocytes plays a critical role on the permeability of the glomerular filtration barrier. Previous studies of the host laboratory have shown that podocytes are mechano-sensitive.
Mechanical stress induces a reversible reorganization of the actin cytoskeleton, accompanied by a change of the gene expression pattern. Gene array analysis allowed the identification of an important matricellular protein, osteopontin (OPN), which is strongly up-regulated by mechanical stress. OPN enhances adaptation of podocytes to mechanical stress by reorganization of the actin cytoskeleton.
The aim of the project is to identify the binding domain of OPN, the OPN receptor, and the signalling cascade activated by OPN in podocytes that mediate mechano-protection. Elucidation of the mechano-protective signalling pathway of OPN in podocytes will provide the basis for the rational design of therapeutics that could mimic the mechano-protective action of OPN.
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