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Role of the MCP-1/CCR2 system in the podocyte alterations of Diabetic Nephropathy: an in vivo and in vitro study


Diabetic Nephropathy (DN) is the commonest cause of renal replacement therapy in the Western World. Hyperglycaemia and hypertension are the major determinants in the pathogenesis of DN and inflammatory mechanisms are believed to contribute to the glomerular damage. The Applicants hypothesis is that the chemokine Monocyte Chemoattractant Protein-1 (MCP-1), which is over-expressed by podocytes in experimental diabetes, plays a key role in the pathogenesis of the alterations characteristic of DN. This will be tested in vivo in diabetic animal knockout for MCP-1 and in vitro in cultured human podocytes.

The Applicant will assess in diabetic mice if the absence of MCP-1 prevents the development of proteinuria, thickening of the glomerular basement membrane, and down regulation of the podocyte protein nephrin. In vitro the Applicant will test whether podocyte exposure to high glucose and/or haemodynamic stress affects the expression of MCP-1 and its receptor CCR2. Further, if MCP-1 has direct deleterious effects in podocytes (e.g. enhanced extracellular matrix production, altered expression of proteins modulating permeability) that help explain the alterations of the diabetic glomerulus.

The Applicant has considerable expertise in vitro work, thus this part of the study will help establish her reputation in the field and reinforce her teaching abilities through supervision of younger scientists. The Applicant has no experience in in vivo/ex vivo work; thus the project will give her the opportunity to acquire new skills (e.g. animal work, tissue processing). This will broaden her area of expertise and allow her to expand her research activity beyond DN. Furthermore, it will enhance her job opportunities and her chances to submit successful research grants, and facilitate the achievement of a leadership position. The opportunity to attend advanced courses and her training in complementary skills will enhance her independence and help launch her research career.

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