Role of Lipocalin-2 as prognostic marker and therapeutic target in kidney transplantation

Lipocalins are involved in immunomodulatory processes, iron transport and cell survival and are thus proposed to be crucial for ischemia and reperfusion injury and rejection episodes following solid organ transplantation. The molecular function of Lipocalin-2 as well as its (possible effects on intracellular signaling pathways) mode of action in the context of these pathophysiological processes is still widely unknown. After having demonstrated a chemotactic effect of Lipocalin-2 on infiltrating neutrophils in a murine transplantation model we now aim at investigating the role of the protein during acute rejection using an approach, which combines human studies with experiments in a murine kidney transplant model to dissect the underlying processes. In a prospective clinical cohort trial of kidney transplantation we attempt to elucidate a possible role of Lipocalin-2 as a prognostic marker of acute rejection and as a diagnostic parameter for the evaluation of graft function in patients undergoing kidney transplantation. To address the possible impact of ischemia and reperfusion injury as well as exogenous application of Lipocalin-2 during kidney transplantation we will employ a well-established murine kidney transplantation model. This will form the basis for a possible therapeutic application of Lipocalin-2 or Lipocalin-2 inhibitors to prevent ischemia and reperfusion injury and acute rejection of transplanted organs.

The clinical and experimental parts of this project investigated the role of Lipcoalin-2 (Lcn2) in kidney transplantation. So far, Lcn2 was demonstrated upregulated in various clinical settings of acute and chronic diseases (e.g. acute kidney injury, chronic inflammatory and rheumatic diseases, septic and cardiac shock). Lcn2 is produced in cells of the innate immune system, tumors and kidney epithelial cells and thus well detectable in urine and blood. Its role in kidney transplantation is still not fully understood. This study could prove a correlation between acute rejection and up-regulation of Lcn2 in blood and urine of kidney transplant recipients. Furthermore a dual function of Lcn2 as upregulated marker during acute rejection and therapeutical agent to prevent acute rejection could be analyzed in a murine kidney transplantation model. These findings give support for a possible future application of Lcn2 as early marker as well as immunosuppressive agent to prevent acute rejection or adjust immunosuppressive regimens in kidney transplantation.