Comparative Analysis of Acute Kidney Injury Models and Related Fibrogenic Responses: Convergence on Methylation Patterns Regulated by Cold Shock Protein
Sabine Brandt,
Anja Bernhardt,
Saskia Häberer,
Katharina Wolters,
Fabian Gehringer,
Charlotte Reichardt,
Anna Krause,
Robert Geffers,
Sascha Kahlfuß,
Andreas Jeron,
Dunja Bruder,
Jonathan A. Lindquist,
Berend Isermann,
Peter R. Mertens
Affiliations
Sabine Brandt
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany
Anja Bernhardt
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany
Saskia Häberer
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany
Katharina Wolters
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany
Fabian Gehringer
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany
Charlotte Reichardt
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany
Anna Krause
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany
Robert Geffers
Genome Analytics Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
Sascha Kahlfuß
Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany
Andreas Jeron
Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany
Dunja Bruder
Medical Faculty, Health Campus Immunology, Infectiology and Inflammation (GCI-3), Otto-von-Guericke University, 39120 Magdeburg, Germany
Jonathan A. Lindquist
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany
Berend Isermann
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig University, 04103 Leipzig, Germany
Peter R. Mertens
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, 39120 Magdeburg, Germany
Background: Fibrosis is characterized by excessive extracellular matrix formation in solid organs, disrupting tissue architecture and function. The Y-box binding protein-1 (YB-1) regulates fibrosis-related genes (e.g., Col1a1, Mmp2, and Tgfβ1) and contributes significantly to disease progression. This study aims to identify fibrogenic signatures and the underlying signaling pathways modulated by YB-1. Methods: Transcriptomic changes associated with matrix gene patterns in human chronic kidney diseases and murine acute injury models were analyzed with a focus on known YB-1 targets. Ybx1-knockout mouse strains (Ybx1ΔRosaERT+TX and Ybx1ΔLysM) were subjected to various kidney injury models. Fibrosis patterns were characterized by histopathological staining, transcriptome analysis, qRT-PCR, methylation analysis, zymography, and Western blotting. Results: Integrative transcriptomic analyses revealed that YB-1 is involved in several fibrogenic signatures related to the matrisome, the WNT, YAP/TAZ, and TGFß pathways, and regulates Klotho expression. Changes in the methylation status of the Klotho promoter by specific methyltransferases (DNMT) are linked to YB-1 expression, extending to other fibrogenic genes. Notably, kidney-resident cells play a significant role in YB-1-modulated fibrogenic signaling, whereas infiltrating myeloid immune cells have a minimal impact. Conclusions: YB-1 emerges as a master regulator of fibrogenesis, guiding DNMT1 to fibrosis-related genes. This highlights YB-1 as a potential target for epigenetic therapies interfering in this process.
