Molecular determinants of progression of chronic kidney disease
Final Report Abstract
Progression of chronic kidney disease towards end-stage renal failure is an unsolved challenge in Nephrology. Fibrosis, an excessive scarring process, which ultimately causes shrunken kidneys in end-stage renal failure is a common pathways of chronic nephropathies. As of now, specific therapies to halt, or even reverse fibrosis are not available in the kidney or any other organ. The main mediators of fibrosis are fibroblasts. While fibroblasts are quiescent within healthy organs they become activated upon tissue injury and proliferate. It is a hallmark of fibrogenesis that fibroblasts continue to proliferate even when the initial stimulus has been contained and even despite mounting DNA damage. In this context, we here studied “Eyes absent homolog 1” (EYA1), a dual phosphatase. We demonstrate that renal fibrosis is associated with alternative splicing of EYA1 and that the new splice variants contribute causally to fibrosis and loss of kidney function. We identified mechanisms, which underlie alternative splicing of EYA1 within the injured kidney. Furthermore, we demonstrate that alternative Splicing of EYA1 causes a shift in phosphatase substrate specificity and that the new variants enable fibroblasts to proliferate even under genotoxic stress within the fibrotic microenvironment.
Publications
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Histopathological Findings Predict Renal Recovery in Severe ANCA-Associated Vasculitis Requiring Intensive Care Treatment. Frontiers in Medicine, 7(2021, 2, 9).
Hakroush, Samy; Tampe, Desiree; Korsten, Peter; Ströbel, Philipp; Zeisberg, Michael & Tampe, Björn
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PP2A phosphatase inhibition is anti-fibrotic through Ser77 phosphorylation-mediated ARNT/ARNT homodimer formation. Scientific Reports, 11(1).
Nyamsuren, Gunsmaa; Rapp, Gregor; Dihazi, Hassan; Zeisberg, Elisabeth M.; Tampe, Desiree; Tampe, Björn & Zeisberg, Michael
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Treatment of aberrant fibroblast proliferation. US20210137963
Zeisberg et al.
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Variable Expression of Programmed Cell Death Protein 1-Ligand 1 in Kidneys Independent of Immune Checkpoint Inhibition. Frontiers in Immunology, 11(2021, 1, 21).
Hakroush, Samy; Kopp, Sarah Birgit; Tampe, Désirée; Gersmann, Ann-Kathrin; Korsten, Peter; Zeisberg, Michael & Tampe, Björn
