Mechanical Ventilation Induces Renal Mitochondrial Injury Detectable by Urine Mitochondrial DNA and ATP Synthase‐β
Authors: Hepokoski Mark Lawrence , Li Ying , Luna Patricia , Fazal Armaan , Mai Tina , Moshensky Alex , Crotty Alexander Laura E. , Singh Prabhleen 
Published: June 2021

Invasive mechanical ventilation for respiratory failure is associated with a threefold increase in the odds of developing acute kidney injury (AKI). The exact mechanisms of AKI due to mechanical ventilation (MV) remain unclear, and no specific biomarkers or therapies exist beyond lung protective ventilation. Mitochondrial dysfunction has recently emerged as a modifiable mechanism of various forms of AKI. We sought to determine if MV would induce mitochondrial dysfunction in the kidney, and if known markers of mitochondrial dysfunction and injury, ATP synthase‐β (ATPβ) and mitochondrial DNA (mtDNA), could be detected in the urine.Sixteen C57BL/6 mice underwent tracheostomy followed by randomization to i) Low tidal volume (LTV) ventilation protocol (7 cc/kg tidal volume, peak end expiratory pressure (PEEP) = 5 cm H20, respiratory rate (RR) = 150/min) ii) High tidal volume (HTV) ventilation protocol (20 cc/kg tidal volume, PEEP = 2.5 cm H20, RR = 75/min) or iii) no MV. At 4 hours, plasma creatinine was determined by mass spectrometry, urine ATPβ and mtDNA were evaluated by Western blot and quantitative PCR, respectively. Whole kidney lysates were evaluated by Western blot for levels of mitochondrial fission protein, Drp1, and mitochondrial fusion protein, Opa1.Drp1 was significantly increased and Opa1 significantly decreased in LTV and HTV ventilation groups compared to no MV group (P<0.05). Drp1 and Opa1 levels did not differ significantly in LTV group compared to HTV group. Plasma creatinine, urine ATPβ, and urine mtDNA were significantly increased after LTV and HTV ventilation compared to no MV mice (p<0.05) (Figure 1). Plasma creatinine was not significantly different in LTV compared to HTV mice, however, there was a significant increase in urine mtDNA in HTV compared to LTV mice (p=0.05), and an increase in urine ATPβ after HTV vs LTV ventilation that nearly reached significance (P=0.08) (Figure 1).Invasive mechanical ventilation led to altered mitochondrial dynamics in the kidney characterized by increased fission and decreased fusion. MV also led to renal mitochondrial dysfunction as demonstrated by increased levels of urine ATPβ and mtDNA in mechanically ventilated mice. Urine ATPβ and mtDNA levels were also increased after a more injurious ventilation strategy (HTV) compared to LTV. Urinary ATPβ and mtDNA warrant further investigation as potential biomarkers that alert clinicians to mechanical ventilation‐induced kidney injury, and mitochondrial function and dynamics warrant further investigation as therapeutic targets to prevent AKI due to MV.Support or Funding InformationThis work was supported by VA Merit BX002175 (PS), R01 DK107852 (PS), R03 DK101841 (PS), T32 DK104717 (supporting MH), VA CDA‐2 1IK2BX001313 (LCA), Pilot and Feasibility Grant (LCA) from UAB‐UCSD O'Brien Center (NIH P30‐DK 079337). There are no competing financial interests.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.