RTG 2408 - Maladaptive processes across physiological barriers in chronic diseases

Project 8

Intimate interaction of monocytes/macrophages with resident kidney cells in maladaptive tubular damage

 

CR2

Charlotte Reichardt

PhD Student

                                

PM2

Prof. Dr. Peter Mertens

Project Leader

Tubular cells are metabolically highly active and responsive to “external stimuli” by direct contact to urine outflow. Activated tubular cells release mediators affecting local and recruited immune cells, aiming to maintain a balanced milieu. However, if errant, these processes lead to maladaptive responses involving tubular cells, pericytes, and endothelial cells resulting in renal fibrosis and vascular rarefication. Our preliminary data demonstrate that cold shock proteins (e.g. YB-1) largely control monocytic cell recruitment to activated tubular cells. The mechanisms through which YB-1 regulates the tubular cell phenotype, e.g. its impact on gene expression and PTMs, remain unknown. Furthermore, the mechanistic relevance of YB-1 for monocyte recruitment, and phenotypic changes, pericyte-phenotype, and peri-tubular capillaries remains unclear. We hypothesize that YB-1 regulates the tubular secretome and thus the peritubular micromilieu, modulating the phenotype of adjacent cells and the recruitment of monocytes in chronic kidney disease. We speculate that YB-1 activity is persistently posttranslationally modulated (e.g. acetylation, ubiquitination). To address these questions we will analyze chronic kidney injury models in mice lacking YB-1 or the YB-1 target Notch3 specifically in tubular cells (cooperation with Project 5). YB-1 dependent gene expression (expression profiling and ChIP analyses) and the tubular secretome (BIOPLEX) will be determined in cooperation with Project 9. The regulation of YB-1 stability and function through post-translational modifications will be analyzed in cooperation with Project 1, Project 2, and Project 7. Structure-function in vitro analyses will be conducted to delineate the mechanistic relevance of these post-translational modifications. Kinetic analyses will enable us to determine the relevance of YB-1 modifications for disease perpetuation. To this end ex vivo approaches with co-culture systems will be conducted (including primary tubular cells from wt and genetically modified mice). The relevance of YB-1 in tubular cells or monocytes for peritubular capillary rarefication will be analyzed in cooperation with Project 4 using state of the art in vivo imaging. In a translational approach human tissue samples will be analyzed to validate the findings.

 

TP8

 

Tubular damage and ensuing inflammatory response

Following tubular cell stress, polarization is lost, chemokines are secreted and immune cells recruited. The latter determine the regeneration process and the extend of tissue inflammation. In maladaptive responses excess chemokine secretion and pro-inflammatory cytokines results in non-reversible tissue scarring and rarefication of peritubular capillaries (Figure modified from Gewin, Zent, & Pozzi, 2017; Kidney International  91, 552–560).

upPhotos: M. Dybiona/University Hospital Magdeburg

Last Modification: 11.02.2020 - Contact Person:

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