Linking polarity signaling to mechanotransduction in glomerular podocytes

• Applicant: Dr. Sybille Köhler
• Subject Area: Nephrology
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424185536

Diseases of the kidney filtration barrier are a major cause of chronic kidney disease affecting more than 500 million people worldwide. Independent of the underlying cause, the degree of glomerular injury is always defined by the damage to the epithelial cells of the glomerulus, the podocytes. The latter are highly specialized epithelial cells of the glomerulus, which build the actual kidney filtration barrier together with fenestrated endothelial cells and the glomerular basement membrane. Podocytes exhibit a unique morphology and form primary and secondary foot processes, which enwrap the glomerular capillaries completely. Upon injury this specialized and functional morphology alters and podocytes resemble classical columnar epithelial cells. As a direct consequence, the podocytes’ cell shape changes and the cells are lost into the primary urine. Given the post mitotic nature of podocytes any cellular loss cannot be compensate by proliferation of neighboring cells leaving the capillaries blank and causing immense loss of protein into the primary urine. The actin-cytoskeleton plays an important role during this dedifferentiation process, but the regulatory pathways are either not identified so far or only characterized insufficiently. Preliminary MS/MS data of injured primary mouse podocytes revealed a significant increase of the putative mechanosensor protein Filamin B upon injury. Its Drosophila homolog Cher was also significantly increased in Drosophila nephrocytes with a defective polarity signaling machinery, suggesting not only a high importance of mechanotransduction processes and cell polarity signaling pathways in podocytes, but also a potential genetic dependency of both pathways. Therefore, within this project proposal we aim to investigate the impact of mechanotransduction and cell polarity signaling on podocyte biology. We will make use of the Drosophila nephrocyte model to further unravel the functional role of the mechanosensor protein Filamin. To this end, we will generate different transgenic flies and characterize the contribution of the different Filamin domains for nephrocyte morphology and function. In a second and independent approach, we will study the impact of aberrant cell polarity signaling on mechanotransduction process in Drosophila nephrocytes in vivo. To further examine the interconnection between the two pathways, we will also analyze effects of disturbed mechanosensation on cell polarity in nephrocytes. Within this proposal, we not only aim to unravel the functional role of Filamin in vivo, but also aim to characterize the potential interconnection between mechanotransduction and cell polarity signaling in nephrocytes in vivo. The findings of this proposal will clearly help to understand the underlying mechanisms regulating morphological changes of podocytes upon injury. Based on this acquired knowledge novel therapies treating glomerular diseases can be developed in the future.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Privatdozent Barry Denholm, Ph.D.