Mitochondrial Function in Long-Term Consequences of Renal Ischemia-Reperfusion Injury

Background Renal tissue hypoxia is a common link between AKI and CKD. The kidney has high mitochondrial oxidative metabolism, and is exquisitely sensitive to hypoxic injury. Mitochondria play a central role in cell injury and their dysfunction has been implicated in early AKI, but limited information is available regarding the long‐term consequences of AKI. Methods We performed 10min and 15min of bilateral renal artery clamping (IR) in mice and then serial GFR measurement by FITC inulin kinetics at days 1, 3, 7, 14 days, 4 weeks and 14 weeks after ischemia and protein expression of mitochondrial oxidative phosphorylation complexes (Ox phos), fission, fusion and AMPK at the same time points. Results Serial GFRs In the 10min group, GFR was significantly lower at days 1 and 3 but improved after that to levels similar in shams. In the 15min group, GFR was dramatically reduced with partial recovery over 4 and 14 weeks. Ox Phos expression Significant reduction in expression for both 10 and 15 min IR at 1–2 weeks for most complexes, with recovery in expression at 4 weeks for 10min, but persistent reduction for 15min IR. Mitochondrial Proteins at 4weeks, 15min IR showed significant reduction in Mfn2 and increase in Fis1 expression. Total AMPK expression was increased at day1, but no increase in pAMPK was seen in the 15min IR kidney. In 10min IR, pAMPK was increased at 24 hrs and persisted at 4 weeks. Conclusions Our findings show duration of IR corresponding with severity of injury and impaired recovery in GFR, and mitochondrial dysfunction with decreased Ox phos proteins and altered dynamics with impaired AMPK activation in IR kidneys, corresponding to severity of injury, but in some instances despite functional recovery. These may be important in transition of AKI to CKD. Additional studies to compare these two models when manipulated with maneuvers to worsen or improve recovery from IR are ongoing. Support or Funding Information NIDDK O'Brien Center for AKI Research P30DK079337. Veterans Affairs (VA) Merit Award BX002175 (P. Singh) NIDDK R03 DK101841 (P.Singh) NIDDK R01 DK107852 (P.Singh)