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

Dietary restriction and fasting arrest B and T cell development and increase mature B and T cell numbers in bone marrow

Dietary restriction (DR) delays ageing and extends life span. Both long- and short-term DR, as well as short-term fasting provide robust protection against many "neuronal and surgery related damaging phenomena" such as Parkinson's disease and ischemia-reperfusion injury. The exact mechanism behind this phenomenon has not yet been elucidated. Its antiinflammatory actions prompted us to thoroughly investigate the consequences of DR and fasting on B and T cell compartments in primary and secondary lymphoid organs of male C57Bl/6 mice. In BM we found that DR and fasting cause a decrease in the total B cell population and arrest early B cell development, while increasing the number of recirculating mature B cells. In the fasting group, a significant reduction in peripheral B cell counts was observed in both spleen and mesenteric lymph nodes (mLN). Thymopoiesis was arrested significantly at double negative DN2 stage due to fasting, whereas DR resulted in a partial arrest of thymocyte development at the DN4 stage. Mature CD3+ T cell populations were increased in BM and decreased in both spleen and mLN. Thus, DR arrests B cell development in the BM but increases the number of recirculating mature B cells. DR also arrests maturation of T cells in thymus, resulting in depletion of mature T cells from spleen and mLN while recruiting them to the BM. The functional relevance in relation to protection against organ damage needs to be determined

Mannan-binding lectin is involved in the protection against renal ischemia/ reperfusion injury by dietary restriction

Preoperative fasting and dietary restriction offer robust protection against renal ischemia/ reperfusion injury (I/RI) in mice.We recently showed that Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, plays a pivotal role in renal I/RI. Based on these findings, we investigated the effect of short-term DR (30% reduction of total food intake) or three days of water only fasting on MBL in 10-12 weeks old male C57/Bl6 mice. Both dietary regimens significantly reduce the circulating levels of MBL as well as its mRNA expression in liver, the sole production site of MBL. Reconstitution of MBL abolished the protection afforded by dietary restriction, whereas in the fasting group the protection persisted. These data show that modulation of MBL is involved in the protection against renal I/RI induced by dietary restriction, and suggest that the mechanisms of protection induced by dietary restriction and fasting may be different. Copyright

PROTECTION AGAINST RENAL ISCHEMIA REPERFUSION INJURY BY DIETARY RESTRICTION AND FASTING THROUGH DOWNREGULATION OF MANNAN-BINDING LECTIN

Nephrolog

DIETARY RESTRICTION AND FASTING PROTECTS AGAINST RENAL ISCHEMIA-REPERFUSION INJURY VIA MBL-PATHWAY

Nephrolog

Dietary restriction and fasting downregulate upstream as well as downstream complement proteins and activity

Nephrolog

Protection Against Renal Ischemia Reperfusion Injury By Dietary Restriction and Fasting Through Downregulation of Mannan-Binding Lectin

Nephrolog

Downregulation of Complement Activity Via the Mannan-Binding Lectin (MBL) Pathway by Dietary Restriction and Fasting

Nephrolog