Characterization of Par3(B) function in glomerular podocytes

• Applicant: Professor Dr. Paul-Thomas Brinkkötter
• Subject Area: Nephrology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 299260418

Diseases of the kidney filter are a leading cause of end stage renal failure with a consecutive rising socio-economic burden. Most known disorders originate from or affect the podocytes, terminally differentiated and highly polarized glomerular epithelial cells that form the outer layer of the kidney filtration barrier. The only cell-cell contact formed by podocytes is the slit diaphragm in between neighboring cells, which is localized at the basal part of the podocyte. The morphological feature of podocyte damage is effacement, the simplification of podocyte architecture with an altered actin based cytoskeleton and disturbed cellular polarity. We and others have shown that the aPKC/Par3/Par6 polarity-signaling complex is part of the slit diaphragm linking cell recognition and polarity signaling pathways. In mammals, there are two Par3 proteins, Par3A and Par3B, which originate from the expression of very different genes. Unpublished data from our group revealed that in contrast to most other renal and non-renal cells Par3B is the predominant Par3 protein in podocytes. While most of our understanding of the Par complex derives from work on Par3A very little is known about Par3B and its specific function. In the current proposal we take advantage of the experimental power of mouse and fly model organisms to (i) delineate the function of Par3B in development and maintenance of the glomerular filtration barrier and (ii) characterize the Par3B interactome and associated signaling pathways. We then propose to examine (iii) the different Par3A and Par3B isoforms and their physiological relevance in nephrocytes from Drosophila melanogaster. We believe, the proposed research project has a high likelihood to yield novel insights into the regulation of polarity signaling in podocytes and bears the potential for novel therapeutic strategies to treat glomerular disease.

• DFG Programme: Research Grants