Intimate interaction of monocytes/macrophages with resident kidney cells in maladaptive tubular damage
Renal tubular epithelial cells release mediators affecting resident adjacent cells and recruited immune cells, which skews the micromilieu. If perpetuated, these processes lead to maladaptive responses involving loss of tubular cell polarization, cell death, and loss of pericytes or endothelial cells (EndC). The resulting renal fibrosis and vascular rarefication will ultimately impair tubular barrier function. Endogenous tubular cell Regeneration is insufficient for renal repair following chronic stimuli. Especially the intimate crosstalk between tubular cells, EndoC, and infiltrating immune cells and the consequences of these interactions for cell fate decisions remain unknown. Our preliminary data demonstrate that cold shock proteins (e.g. Y-box binding protein-1 (YB-1) and DNA binding protein-A (DbpA)) control monocytic cell recruitment to activated tubular cells and have prominent effects on tubular cell phenotypes and survival. Intriguingly, the role of YB-1 is highly context specific, as mice with whole body YB-1 depletion show diametrical responses to different stresses: following
ischemia/reperfusion the tubular damage is enhanced, whereas following tubular obstruction tubular damage is reduced. Notably, when a known receptor for extracellular YB-1 is missing (Notch-3), tubular cells are non-responsive to common cell stress and lack NF- B activation. Collectively, these observations suggest that YB-1 controls renal cell fate in a highly cell- and /or context-specific fashion in part via Notch-3. Dedifferentiation of tubular cells is thought to contribute to renal repair. Dedifferentiated tubular cells highly express DbpA, whereas differentiated cells do not. In addition, enhanced tubulointerstitial fibrosis is dependent on DbpA expression. The mechanisms through which cold shock proteins regulate tubular cell phenotype, the crosstalk with adjacent resident/infiltrating cells, and the function of the tubular barrier in chronic renal dysfunction will be the focus of this Project.