Participation of cold shock DNA-binding protein-A in inflammatory kidney diseases

• Applicant: Professor Dr. Peter Rene Mertens
• Subject Area: Nephrology
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260632335

DNA binding protein-A (DbpA) belongs to the human cold shock protein superfamily with known functions related to fibrogenesis, cancerogenesis and transcriptional/translational regulation. Evidences link DbpA with an activated, proliferative tubular cell phenotype. Beyond its participation in tight junction-related complex formation, our data suggest mitochondrial and exosomal functions. Furthermore, DbpA protein is actively secreted, e.g. in mesangioproliferative nephritis. The combined effects of two cold shock proteins, Y-box binding protein-1 (YB-1) and DbpA, results in an invasive, pro-migratory cell phenotype. The current proposal focuses on inflammatory kidney diseases (such as unilateral ureteral nephropathy, nephrotoxic nephritis and diabetic nephropathy) and aims to investigate the functional role(s) and participation of DbpA. We will determine (i) functions fulfilled by intra- and extracellular DbpA. For intracellular DbpA its participation in mitochondrial energy homeostasis will be clarified. Furthermore a search for cell surface receptors will be set up that may affect intracellular signaling/cell fate decision. (ii) Having identified an overlap in the interactome of DbpA and YB-1, we will characterize extra- and intracellular interactions of both proteins and relate these to functions. Additionally the contribution of exosomal DbpA to cell proliferation, pro-inflammatory and -fibrotic cell phenotypes will be investigated. (iii) We will clarify how genetic ablation of DbpA affects the inflammatory response/outcome of kidney diseases. (iv) Finally, preliminary data indicate that DbpA expression levels in leukocytes is highly regulated, at the same time serum contains significant protein amounts. Our quest is to determine by which stimuli the DbpA expression is regulated in circulating immune cells. Given autoimmune responses against cold shock proteins are established we will test for autoantibodies against DbpA.The proposal addresses pivotal questions on the functional role(s) of the cold shock protein DbpA in the pathogenesis of inflammatory kidney diseases. Given the marked cellular effects seen with modification of DbpA expression in mesangial and tubular cells our quest is to harness the findings to develop diagnostic and therapeutic strategies.

• DFG Programme: Research Grants