NIV Congres

Background Seventy-two hours of preoperative fasting (F) or 2 weeks of 30% dietary restriction (DR) offers robust protection against renal ischemia-reperfusion injury (IRI) in mice. However, the mechanism remains to be elucidated. We hypothesize that immunomodulation plays a pivotal role. Innate immunity, especially the complement system, is crucial in the pathophysiology of IRI. Therefore, we investigated the impact of F and DR on complement activation pathways.

Materials and Methods Male C57Bl/6 mice were fed ad libitum (AL) or underwent 72 hours F or 30% DR for 2 weeks (n=8/group), after which blood was drawn and serum was aliquoted and stored at -80^oC. Functional activity of the complement activation pathways (classical (CP), lectin (LP) and alternative pathway (AP)) was assessed by ELISA using immobilized ligands. Deposition of C3 and C9 as a measure of complement activity along with concentration of upstream complement initiating proteins (Mannan-binding lectin (MBL)-A and –C, and C1q) was determined. Messenger RNA studies were also performed on both kidney and liver tissues of the experimental mice for all the important upstream and downstream complement proteins.

Results A significant downregulation in CP and LP activity by DR and in CP, LP and AP activity by F was observed compared to the AL group. The activation of both C3 and C9 in the DR and F group was significantly downregulated (p≤0.002) in CP, LP and AP (except for C3 activation in the AP of the dietary restriction group). Both MBL-A and –C concentrations were significantly lower (p≤0.001) after DR and F compared to that of AL group. C1q concentration was only significantly lower in the fasted group (p≤0.0001). The mRNA studies showed that there was a significant downregulation in the liver MBL expression in both DR and F (p≤0.004) groups. However, C3 mRNA levels (both in kidney and liver) were found to be elevated in both DR (p≤0.03) and F (p≤0.05) groups. 

Conclusion Dietary interventions downregulate complement activation pathways. The most prominent effect of DR and F was observed on the MBL pathway.  To our knowledge, our data for the first time show that DR and F cause downregulation of complement activation pathways. We conclude that complement downregulation via the MBL pathway may be one of the mechanisms by which dietary interventions protect against renal IRI.