Kidney Keratins, endogenous cytoprotective factors?

• Applicant: Professor Peter Boor, Ph.D.
• Subject Area: Nephrology ; Pathology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318056912

Keratins (K) are intermediate filaments (IFs) and a major component of the cell cytoskeleton of epithelial cells, providing for their mechanical integrity. Keratins also have cytoprotective functions in a variety of stress situations, best described for skin and the gastrointestinal tract. Tubular cells (TEC) are the most abundant renal epithelial cells. During virtually all kidney diseases TEC are exposed to a number of stress stimuli, to which they react by phenotypic alterations and cytoskeletal remodeling. We recently showed that the major renal keratins, i.e. K7, K8, K18 and K19, are highly up-regulated in different animal models and patients with kidney injury and could serve as novel markers of TEC stress. We hypothesize, that keratins may play a major cytoprotective role during the accommodation of TEC to a broad array of stress situations and that they promote TEC repair. We aim to tackle this hypothesis in the following work packages:1. We will compare wild-type and various keratin-deficient primary murine TEC in vitro with respect to biomechanical properties, phenotypic and pro-inflammatory alterations, regenerative potential and survival.2. In vivo, we will analyze the consequences of deletion of the whole keratin II gene cluster specifically in TEC or of single major renal keratins in healthy mice and in several renal disease models characterized by TEC injury and regeneration. 3. We will use the K8-eYFP reporter mice to analyze the dynamics of keratin filaments in vitro and in vivo.4. Finally, we aim to identify the post-translational modifications and potential novel kidney keratins and test the usefulness of keratins as specific urinary markers of TEC injury.These experiments will provide first data on the functional role and diagnostic potential of renal keratins.

• DFG Programme: Research Grants