Metabolic deregulation, genome instability, and the progression of chronic kidney disease

Chronic kidney disease (CKD) is a global health burden that affects 10-15% of the population. Moreover, CKD has been identified as a major risk factor for cardiovascular mortality. CKD can result from various different renal disorders and is characterized by loss of functional renal tubules, loss of renal microvasculature, and progressive fibrosis. Recent clinical, genetic and experimental evidence suggested genome instability in renal tubular epithelial cells as a critical pathogenic factor in renal fibrosis and CKD progression. Notably, accumulation of DNA damage has also been observed in extra-renal cells in CKD, indicating systemic effects of CKD on genome stability.

We hypothesize that the accumulation of unresolved DNA damage and the resulting transcriptomic, epigenetic and metabolic changes form a vicious circle and represent the main driving forces of renal fibrosis and CKD progression. Therefore, the overarching aim of this project is to analyze the interplay of genome instability and transcriptional and metabolic deregulation in the pathogenesis of CKD. Based on well-established mouse models we aim to gain mechanistic insights into genome instability as a driver of kidney disease. To this end, we will characterize metabolic, transcriptomic, and epigenetic alterations caused by DNA damage in the kidney and analyze the effects of dietary interventions on disease progression. Specifically, we will (1) analyze how defects in DNA repair may affect genomic stability causing renal fibrosis and end-stage-renal failure, (2) address signaling networks involved in genome maintenance in the kidney, and (3) study the interplay between altered metabolism and renal function loss and genomic instability in disease progression. Ultimately, we aim to develop strategies for future clinical applications targeting renal genome instability and preventing CKD.

PROJECT RELATED PUBLICATIONS

Koehler, F.C., Fu, C.Y., Spath, M.R., Hoyer-Allo, K.J.R., Bohl, K., Gobel, H., Lackmann, J.W., Grundmann, F., Osterholt, T., Gloistein, C., Steiner, J.D., Antebi, A., Benzing, T., Schermer, B., Schwarz, G., Burst, V., and Muller, R.U. (2022). A systematic analysis of diet-induced nephroprotection reveals overlapping changes in cysteine catabolism. Transl Res. 2022 Feb 18 (in press; PMID: 35189406; DOI: 10.1016/j.trsl.2022.02.003)
Jain, M., Kaiser, R.W.J., Bohl, K., Hoehne, M., Gobel, H., Bartram, M.P., Habbig, S., Muller, R.U., Fogo, A.B., Benzing, T., Schermer, B., Hopker, K., and Slaats, G.G. (2019). Inactivation of Apoptosis Antagonizing Transcription Factor in tubular epithelial cells induces DNA damage and nephronophthisis accumulation. Kidney Int 95, 846-858.
Kaiser, RWJ., Ignarski, M., Van Nostrand, EL., Frese, CK., Jain, M., Cukoski, S., Heinen, H., Schaechter, M., Seufert, L., Bunte, K., Frommolt, P., Keller, P., Helm, M., Bohl, K., Höhne, M., Schermer, B., Benzing, T., Höpker, K., Dieterich, C., Yeo, GW., Müller, RU., Fabretti, F. (2019). A protein-RNA interaction atlas of the ribosome biogenesis factor AATF. Sci Rep 9, 1171.
Welcker, D., Jain, M., Khurshid, S., Jokic, M., Hohne, M., Schmitt, A., Frommolt, P., Niessen, C.M., Spiro, J., Persigehl, T., Wittersheim, M., Buttner, R., Fanciulli, M., Schermer, B., Reinhardt, H.C., Benzing, T., and Hopker, K. (2018). AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer. Oncogene 37, 1503-1518.
Braun, F., Rinschen, M.M., Bartels, V., Frommolt, P., Habermann, B., Hoeijmakers, J.H., Schumacher, B., Dolle, M.E., Muller, R.U., Benzing, T., Schermer, B., and Kurschat, C.E. (2016). Altered lipid metabolism in the aging kidney identified by three layered omic analysis. Aging (Albany NY) 8, 441-457.
Schermer, B., Bartels, V., Frommolt, P., Habermann, B., Braun, F., Schultze, J.L., Roodbergen, M., Hoeijmakers, J.H., Schumacher, B., Nurnberg, P., Dolle, M.E., Benzing, T., Muller, R.U., and Kurschat, C.E. (2013). Transcriptional profiling reveals progeroid Ercc1(-/Delta) mice as a model system for glomerular aging. BMC Genomics 14, 559.
Hopker, K., Hagmann, H., Khurshid, S., Chen, S., Hasskamp, P., Seeger-Nukpezah, T., Schilberg, K., Heukamp, L., Lamkemeyer, T., Sos, M.L., Thomas, R.K., Lowery, D., Roels, F., Fischer, M., Liebau, M.C., Resch, U., Kisner, T., Rother, F., Bartram, M.P., Muller, R.U., Fabretti, F., Kurschat, P., Schumacher, B., Gaestel, M., Medema, R.H., Yaffe, M.B., Schermer, B., Reinhardt, H.C., and Benzing, T. (2012). AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis. EMBO J 31, 3961-3975.