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In vitro evaluation of molecular consequences of albumin overload in podocytes

Abstract

Proteinuria is a health problem that affects millions of people around the world, being an important sign and prognostic marker for chronic kidney disease (CKD). Proteinuria usually reflects an increase for albumin permeability in the glomerular filtration barrier (GFB). GFB consists of three main layers: fenestrated endothelium, glomerular basement membrane and the visceral epithelial cells called podocytes. Podocytes are highly specialized cells whose foot processes interdigitate with each other, forming the slit diaphragms (SD). Foot processes have three main domains, the SD, the apical membrane domain (AMD) and the basal membrane domain (BMD). Proteins expressed in these domains have crucial roles in both cell signaling and regulation of the actin cytoskeleton dynamics. Damages to any of the three domains lead to a characteristic response, with foot process effacement and rearrangement of the actin cytoskeleton. It is already known that the effacement contributes to progressive albuminuria, however, there are controversies regarding the impact of proteinuria on worsening the effacement in podocytopathies. Several molecules participate in the maintenance of GFB, including the transient receptor potential channel 6 (TRPC6) and the CD2-associated protein (CD2AP) present in the SD domain, the integrins ±3²1e±½²3 in the BMD, and podocalyxin, a cell surface sialomucin present in the AMD. There are few studies on the molecular consequences of prolonged exposure to albumin overload in human podocytes in vitro. Therefore, the main aims of the present project are: 1) To identify if there is change of expression of TRPC6, CD2AP, ITGA3, ITGB1, ITGAV, ITGB3 and PODXL genes after albumin overload (BSA) in human podocytes with or without previous damage induced by puromycin aminoglycoside (PAN) and, in cases where there is any change, identify potential recovery of the phenotype after removal of albumin overload; 2) To identify the alteration of podocyte adhesion after albumin overload in podocytes with or without previous damage with PAN, and, when a change of adhesion is found, identify the potential recovery of adhesion after removal of albumin overload. Based on this study, molecular pathways should be delineated for future animal model studies that could be potential therapeutical targets contributing to the deceleration of CKD progression in many patients. (AU)

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