Endothelin in organ transplantation

Solid organ allografts are often compromised by ischemia, acute rejection episodes associated with hemodynamic changes, and chronic rejection typically characterized by the development of obliterative vasculopathy, and in the case of the kidney, and glomerulosclerosis. Recent in vivo data indicate that endothelin (ET) production is locally upregulated in rejecting allografts, and that, in addition to endothelial cells, ET is also produced by graft-infiltrating mononuclear cells (monocytes/macrophages). In vitro data also indicate that ET production is regulated, at least in part, by certain T cell-and monocyte/macrophage-derived cytokines, which are abundant in rejecting allografts. These data and the findings of elevated plasma levels of ET after transplantation (in particular during rejection processes), the effects of immunosuppressive drugs (cyclosporine and tacrolimus in particular) on ET production, and the profound vasoconstrictive and mitogenic properties of this peptide suggest that endothelin may be involved in the initiation and propagation of posttransplantation complications; including systemic hypertension, acute allograft dysfunction, and perhaps most importantly, chronic allograft dysfunction. These observations provide the rational to use ET receptor antagonists to formally address the potential role of ET in these processes, and to develop therapeutic strategies that ameliorate or possibly prevent these complications.