The majority of cases of steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) in childhood and adolescence is caused by mutations in single genes. While the probability of single-gene causes of FSGS declines with age there is a clear role for genetic susceptibility also in sporadic forms of FSGS in adulthood. Although the past two decades have witnessed spectacular breakthroughs in the understanding of the genetic basis of SRNS/FSGS, almost 20 years after the description of gene defects in the genes encoding for the slit diaphragm proteins nephrin and podocin the ultimate steps leading to SRNS/FSGS are far from being understood. The overall aim of this research project is to elucidate the pathogenic mechanisms of podocyte foot process effacement (and SRNS) and progressive loss of podocytes (and FSGS) in patients with NPHS2 (podocin) mutations as well as in situations of alterations of slit diaphragm signaling in general. The project follows a three-pronged approach and is based on breakthrough technical achievements that were possible over the past few years. We will elucidate how human pathogenic mutations impact on podocyte signaling, the integrity of the slit diaphragm and proteostasis mechanisms, analyze how Nphs2 mutations impact on mechano-biology of the podocyte with a specific view on how mechanosensor signaling influences cell behaviour and cell fate decisions, cytoskeletal regulation, and genetic programs of phenotypic plasticity, and study how subtle genetic alterations (heterozygous or combined heterozygous mutations of the Nphs2 gene) may predispose podocytes to injury, FSGS and renal failure.
Project related publications
Koehler, S., Brahler, S., Braun, F., Hagmann, H., Rinschen, M.M., Spath, M.R., Hohne, M., Wunderlich, F.T., Schermer, B., Benzing, T., Brinkkötter, PT. Construction of a viral T2A-peptide based knock-in mouse model for enhanced Cre recombinase activity and fluorescent labeling of podocytes. Kidney Int 2017 91, 1510-1517.
Rinschen, M.M., Bharill, P., Wu, X., Kohli, P., Reinert, M.J., Kretz, O., Saez, I., Schermer, B., Hohne, M., Bartram, M.P., Aravamudhan, S., Brooks, BR., Vilchez, D., Huber, TB., Müller, RU., Krüger, M., Benzing, T. The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes. Hum Mol Gen 2016 25, 1328-44.
Rinschen, M.M., Benzing, T., Limbutara, K., and Pisitkun, T. Proteomic analysis of the kidney filtration barrier--Problems and perspectives. Proteomics Clin Appl 2015 9, 1053-1068.
Rinschen, M.M., Wu, X., Konig, T., Pisitkun, T., Hagmann, H., Pahmeyer, C., Lamkemeyer, T., Kohli, P., Schnell, N., Schermer, B., Dryer, S., Brooks, BR., Beltrao, P., Krueger, M., Brinkkoetter, PT., Benzing, T. Phosphoproteomic analysis reveals regulatory mechanisms at the kidney filtration barrier. J Am Soc Nephrol 2014 25, 1509-1522.
Brinkkoetter, P.T., Ising, C., and Benzing, T. The role of the podocyte in albumin filtration. Nat Rev Nephrol 2013 9, 328-336.
Hackl, M.J., Burford, J.L., Villanueva, K., Lam, L., Susztak, K., Schermer, B., Benzing, T., and Peti-Peterdi, J. Tracking the fate of glomerular epithelial cells in vivo using serial multiphoton imaging in new mouse models with fluorescent lineage tags. Nature Med 2013 19, 1661-1666.
Schermer, B., and Benzing, T. Lipid-protein interactions along the slit diaphragm of podocytes. J Am Soc Nephrol 2009 20, 473-478.
Huber, T.B., Schermer, B., Muller, R.U., Hohne, M., Bartram, M., Calixto, A., Hagmann, H., Reinhardt, C., Koos, F., Kunzelmann, K., Shirokova, E., Krautwurst, D., Harteneck, C., Simons, M., Pavenstädt, H., Kerjaschki, D., Thiele, C., Walz, G., Chalfie, M., Benzing, T. Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels. Proc Natl Acad Sci USA 2006 103, 17079-17086.
Huber, T.B., and Benzing, T. The slit diaphragm: a signaling platform to regulate podocyte function. Curr Nephrol Hypert 2005 14, 211-216.
Benzing, T. Signaling at the slit diaphragm. J Am Soc Nephrol 2004 15, 1382-1391.