The goal of this application is to define the molecular mechanisms whereby the modulation of hic-5 protein expression in podocytes causes proteinuria, thereby paving the road for the development of novel anti-proteinuric treatment options.

• Applicant: Dr. Samy Hakroush
• Subject Area: Nephrology
• Term: from 2011 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 200634487

Podocytes are unique cells with a complex cellular organization consisting of a cell body, major processes and foot processes (FPs). The FPs cover the outer aspect of the glomerular basement membrane (GBM). They form a characteristic interdigitating pattern with FPs of neighboringpodocytes, leaving in between the filtration slits that are bridged by the glomerular slit diaphragm (SD). Podocyte dysfunction, represented by FP effacement, disruption of the SD and proteinuria, is often the starting point for progressive kidney disease. Mutations affecting several proteins lead to the rearrangement of the podocyteactin cytoskeleton, disruption of the filtration barrier and subsequent renal disease. Proteins regulating the plasticity of podocyte FPs are therefore of critical importance for sustained function of the glomerular filter.The extracellular matrix receptor integrin a3b1 plays an important role in the formation and maintenance of the kidney filtration barrier. Of note, podocyte defects in integrin a3 deficient (a3-/-) mice resemble those observed in nephrotic syndrome. Podocytes of a3-/- mice are unable to maintain normal podocyte structure, including the elaboration of mature foot processes. Based on novel findings with a3-/-podocytes, the host laboratory identified a physiological role for hic-5, a senescence and hypertrophy-promoting member of the paxillinsuperfamily member, as inducible modifier of glomerular permselectivity. The preliminary data presented below suggest that the integrin a3-dependent replacement of paxillin by hic-5 provides a critical switch in podocyte adhesion to the GBM, thereby contributing to the pathogenesis and progression of proteinuric kidney diseases.The goal of this application is to define the molecular mechanisms whereby the modulation of hic-5 protein expression in podocytes causes proteinuria, thereby paving the road for the development of novel anti-proteinuric treatment options.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Peter Mundel