Kidney transplantation (KTx) stands as the sole curative treatment option for individuals afflicted with end-stage renal disease, providing them a renewed opportunity for kidney function. However, the success of KTx is hindered by immune-mediated graft rejection, occurring both in the early postoperative phase and over the long term. These rejections episodes profoundly affect graft function and survival, posing significant challenges to successful transplantation outcomes. Lipocalin-2 (Lcn2), a member of lipocalin family, has received substantial recognition in the field of kidney transplantation due to its pivotal role in diverse physiological processes, such as iron transport, bacterial defence, and regulation of immune responses. Studies have shown that Lcn2 expression is upregulated in renal allografts during acute rejection episodes, suggesting its involvement in the immune response against the graft. Furthermore, preclinical studies have demonstrated the potential of exogenously administered recombinant Lcn2 (rLcn2) in ameliorating kidney injury and promoting graft survival. The primary objective of this research was to explore the intricate molecular and cellular mechanisms that underlie the renoprotective effects of rLcn2 in a mouse model of kidney transplantation. Treatment with rLcn2 during the perioperative period led to significant alterations in both adaptive and innate immune cell populations, particularly impacting the functionality and degranulation capacities of immune cells within the kidney graft. Moreover, an effective method for isolating and culturing primary proximal tubular epithelial cells (PTEC) was established to investigate their response to treatment with rLcn2. However, the PTEC exhibited diverse gene expression patterns during the culturing process and early on signs of beginning dedifferentiation processes, indicating two possible cellular fates for the cultured cells: a mesenchymal-like and an epithelial-like state. Furthermore, our investigations identified injured proximal straight tubule cells and stressed intermediate state dendritic cells/macrophages as the principal sources of endogenous Lcn2, providing insights into the cellular dynamics involved in Lcn2 production during allograft rejection. By elucidating the effects of rLcn2 on immune cells and uncovering the cellular origins of Lcn2 expression, this study enhances our understanding of how rLcn2 exerts its renoprotective effects in kidney transplantation. These findings contribute to the growing body of knowledge surrounding Lcn2 as a promising therapeutic target for mitigating immune-mediated damage to the kidney grafts and improving their outcomes.
