Regardless of the underlying etiology, podocytes exhibit a uniform alteration in cellular morphology in pathological conditions of focal segmental glomerulosclerosis (FSGS). While one of the earliest detectable changes is characterized as a prominent retraction and simplification of the podocyte foot process network, increasing detachment of podocytes from the glomerular basement membrane is observed at later stages.
Despite significant progress, a comprehensive understanding of the adhesion-cytoskeletal nexus and its dedicated role in the pathogenesis of FSGS is lacking. Here, our overarching goal is to characterize dynamic alterations of the podocyte adhesome and to investigate their impact in the context of FSGS. For this purpose, we will combine high-resolution proteomics and multidimensional imaging approaches to describe alterations in adhesome signatures in different stages and models of FSGS. In addition, we will employ novel inducible mouse models to investigate how mechano-physical adaptation of podocytes is required to prevent podocyte detachment.
PROJECT RELATED PUBLICATIONS
Rogg, M., Maier, J.I., Dotzauer, R., Artelt, N., Kretz, O., Helmstadter, M., Abed, A., Sammarco, A., Sigle, A., Sellung, D., Dinse, P., Reiche, K., Yasuda-Yamahara, M., Biniossek, M.L., Walz, G., Werner, M., Endlich, N., Schilling, O., Huber, T.B., and Schell, C. (2021) SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance. J Am Soc Nephrol, 32(3): 563-579.
Maier, J.I., Rogg, M., Helmstadter, M., Sammarco, A., Walz, G., Werner, M., and Schell, C. (2021) A Novel Model for Nephrotic Syndrome Reveals Associated Dysbiosis of the Gut Microbiome and Extramedullary Hematopoiesis. Cells, 10(6).
Maier, J.I., Rogg, M., Helmstadter, M., Sammarco, A., Schilling, O., Sabass, B., Miner, J.H., Dengjel, J., Walz, G., Werner, M., Huber, T.B., and Schell, C. (2021) EPB41L5 controls podocyte extracellular matrix assembly by adhesome-dependent force transmission. Cell Rep, 34(12): 108883.
Brinkkoetter, P.T., Bork, T., Salou, S., Liang, W., Mizi, A., Ozel, C., Koehler, S., Hagmann, H.H., Ising, C., Kuczkowski, A., Schnyder, S., Abed, A., Schermer, B., Benzing, T., Kretz, O., Puelles, V.G., Lagies, S., Schlimpert, M., Kammerer, B., Handschin, C., Schell, C., and Huber, T.B. (2019) Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics. Cell Rep, 27(5): 1551-1566 e5.
Yasuda-Yamahara, M., Rogg, M., Yamahara, K., Maier, J.I., Huber, T.B., and Schell, C. (2018) AIF1L regulates actomyosin contractility and filopodial extensions in human podocytes. PLoS One, 13(7): e0200487.
Yasuda-Yamahara, M., Rogg, M., Frimmel, J., Trachte, P., Helmstaedter, M., Schroder, P., Schiffer, M., Schell, C., and Huber, T.B. (2018) FERMT2 links cortical actin structures, plasma membrane tension and focal adhesion function to stabilize podocyte morphology. Matrix Biol, 68-69: 263-279.
Schell, C., Sabass, B., Helmstaedter, M., Geist, F., Abed, A., Yasuda-Yamahara, M., Sigle, A., Maier, J.I., Grahammer, F., Siegerist, F., Artelt, N., Endlich, N., Kerjaschki, D., Arnold, H.H., Dengjel, J., Rogg, M., and Huber, T.B. (2018) ARP3 Controls the Podocyte Architecture at the Kidney Filtration Barrier. Dev Cell, 47(6): 741-757 e8.
Schell, C., Rogg, M., Suhm, M., Helmstadter, M., Sellung, D., Yasuda-Yamahara, M., Kretz, O., Kuttner, V., Suleiman, H., Kollipara, L., Zahedi, R.P., Sickmann, A., Eimer, S., Shaw, A.S., Kramer-Zucker, A., Hirano-Kobayashi, M., Abe, T., Aizawa, S., Grahammer, F., Hartleben, B., Dengjel, J., and Huber, T.B. (2017) The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier. Proc Natl Acad Sci U S A, 114(23): E4621-E4630.
