Sirolimus inhibits lymphangiogenesis in rat renal allografts, a novel mechanism to prevent chronic kidney allograft injury.

Lymphangiogenesis occurs in renal allografts and it may be involved in the maintenance of the alloreactive immune response and thus participate in the development of chronic kidney allograft injury. Sirolimus (SRL) has been shown to inhibit lymphangiogenesis. The aim of this study was to describe lymphangiogenesis and its regulation during the development of chronic kidney allograft injury and to investigate the effect of SRL on allograft lymphangiogenesis and chronic kidney allograft injury. A rat renal transplantation model was used. Allografts treated with cyclosporine A or with SRL were analyzed in various time points. Syngenic transplantations were used as controls. Kidney function was followed with serum creatinine. Histology was analyzed by Chronic Allograft Damage Index (CADI). Immunohistochemistry was used to detect lymphatic vessels, VEGF-C and VEGFR-3. In cyclosporine-treated allografts VEGF-C/VEGFR-3 pathway was strongly upregulated leading to extensive lymphangiogenesis 60 days after transplantation. Lymphangiogenesis correlated positively with the CADI score. Sirolimus efficiently inhibited lymphangiogenesis, improved graft function and attenuated the development of chronic kidney allograft injury when compared with cyclosporine. In conclusion, lymphangiogenesis is associated with chronic kidney allograft injury and SRL is a potent inhibitor of lymphangiogenesis in renal allografts. Inhibition of lymphatic proliferation could mediate the nephroprotective properties of SRL.