Immunomodulation by Dietary Restriction in Renal Ischemia/Reperfusion Injury

Kidney transplantation is considered to be the only curative treatment for people with end stage renal disease. Its results however, are negatively affected by the development of ischemia-reperfusion injury (I/RI) during transplantation. Nowadays, many deceased donor organs come from donors with higher age or comorbidity (extended criteria donor organs) that are more prone for I/RI. I/RI is one of the major causes of ischemic acute renal failure, and is the major cause of delayed graft function. Despite advances in the renal replacement therapy treatment of I/RI is still unsatisfactory. Several lines of evidence support free reactive oxygen species formation, endothelial dysfunction, and immune activation as the crucial event in the development of tissue injury and graft dysfunction during renal I/RI. Recently, mouse studies have shown that dietary restriction (DR) exerts beneficial effects against the detrimental effects of I/RI. Preoperative short term DR and fasting (FA) induce protection against I/RI in both kidney and liver. The exact mechanism behind protection afforded by DR has not been elucidated so far. However, DR regimens have been postulated to reprogram the immunological profile, and increase plasma corticosterone concentrations due to induction of hypothalamic-pituitary-adrenal axis activity. Apart from that, DR has also been considered a mild stressor that ultimately leads to protection, commonly referred to as hormesis and has been hypothesized to be responsible in ameliorating I/RI. Another type of hormesis cold exposure, has been known to induce hypothalamic-pituitary-adrenal axis activity since it results in elevated plasma adrenocorticotropic hormone and corticosterone concentrations.

This thesis describes the immunological changes following DR and FA, and after renal I/RI, with emphasis on both adaptive and innate immunity. We also studied cold exposure as stress model that could potentially induce protection against IRI. Studies presented in this thesis have successfully elucidated the immunological effects of both DR and FA. We have shown that two different short-term dietary interventions cause alterations in all the lymphoid compartments. We showed arrest of the major development stages in both B and T cells. We also highlighted the role played by FA on MBL in the protection against renal I/RI. Furthermore, we showed that not only MBL but also other complement pathways such as terminal pathway play an important role in protection by DR and FA. Our studies show that another stress model, cold exposure, brings about major immunological and metabolic changes but does not induce protection against I/RI. In our studies we could show immunomodulation by dietary restriction but we have not been able to elucidate the exact mechanism behind protection by these dietary interventions. Therefore the role of these immunological effects of dietary interventions in relation to protection against renal I/RI warrants further investigation.