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

Abstract

Introduction Ischemia-reperfusion injury (IRI) remains an important problem in transplantation. We recently showed that Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, plays a pivotal role. Preoperative dietary restriction (DR) offers robust protection against renal IRI in mice. However, the mechanism remains to be elucidated. Therefore, we investigated the impact of DR on MBL and the role of MBL in the protective mechanism of DR. Materials and Methods Male C57Bl/6 mice were fed ad libitum (AL) or underwent 72hrs fasting (FA) or 2 weeks 30%DR (n=8/group). Protein and functional activity of serum MBL-A and -C after DR were assessed as well as liver mRNA analysis. In vivo, IRI was induced by 37 min of bilateral clamping of the renal pedicles in all three groups. After clamping, mice were sutured and part of them was reconstituted via intraperitoneal injection of 100 μg/ml of human MBL. All mice were subsequently observed for a period of 7 days. Results Assessment of mRNA showed a significant downregulation in liver MBL expression in both 30%DR and FA (p≤0.004) groups. In line with this, both MBL-A and MBL-C concentrations were significantly lower (p≤0.001) after 30% DR (A=15.4 μg/ml; C=89.4 μg/ml) and FA (A=12.4 μg/ml; C=49.5 μg/ml) compared to respectively 19.9 μg/ml MBL-A and 109.6 μg/ml MBL-C in the AL group. Furthermore, we observed a significant downregulation of lectin pathway activity in both groups. Importantly, reconstitution of MBL following reperfusion breaks DR-induced protection against renal IRI in the 30%DR group, but not in the FA group. Conclusion Dietary interventions downregulate the expression and presence of MBL. Reconstitution of MBL following reperfusion breaks DR-induced protection and strongly suggests that downregulation via the lectin pathway may be one of the mechanisms by which dietary interventions protect against renal IRI.