Dissertation/Thesis Abstract

Renal mitochondrial dysfunction: Novel therapeutic targets to treat sepsis induced acute kidney injury
by Patil, Naeem K., Ph.D., University of Arkansas for Medical Sciences, 2014, 192; 3633757
Abstract (Summary)

Sepsis-mediated multi-organ failure is frequently associated with acute kidney injury (AKI). In the US alone, sepsis causes ∼ 215,000 deaths annually and a healthcare burden of ∼ $17 billion. As many as 50% of septic patients develop AKI and this increases mortality from 25% to 75%. Currently, there are no effective therapies to treat or prevent sepsis and clinicians must rely only on supportive care. There is a need to identify novel therapeutic targets to treat septic AKI. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis induced multi-organ failure, but the importance of mitochondrial dysfunction in renal injury during sepsis has not been well studied. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis to assess renal mitochondrial function. As early as 4h after CLP, the activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained until 36h without a change in its protein concentration. This finding implied a post-translational modification of MnSOD leading to its inactivation. Further studies revealed that MnSOD inactivation occurred through a novel thiol based mechanism. Renal MnSOD inactivation during sepsis was associated with increased mitochondrial superoxide levels, implying compromised mitochondrial antioxidant defense. CLP also caused a time-dependent decrease in renal mitochondrial complex I and II/III respiration and a reduction in renal ATP levels. "Therefore, I hypothesize that renal mitochondrial dysfunction plays an important role in development of sepsis induced AKI. Furthermore, pharmacological targeting of mitochondrial oxidants can improve renal function and reduce mortality, even with clinically relevant delayed therapy ". The mitochondrial antioxidant, Mito-TEMPO, given at 6h post CLP improved the renal microcirculation, decreased oxidative stress, protected complex I and II/III respiration and restored MnSOD activity. Importantly, delayed therapy with Mito-TEMPO significantly increased the 96h survival rate from 40% in untreated septic mice to ∼83%. These data show that mitochondrial dysfunction is a critical event in sepsis induced AKI and even delayed therapy with the mitochondria-targeted antioxidant, Mito-TEMPO, represents a promising approach to treat septic AKI.

Indexing (document details)
Advisor: MacMillan-Crow, Lee Ann, Mayeux, Philip R.
Commitee: James, Laura P., Rusch, Nancy J., Tackett, Alan J.
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Toxicology
School Location: United States -- Arkansas
Source: DAI-B 76/01(E), Dissertation Abstracts International
Subjects: Pharmacology, Medicine, Health sciences
Keywords: Kidney, Mitochondria, Sepsis
Publication Number: 3633757
ISBN: 9781321138788
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