Sepsis is a serious medical condition characterized by a severe systemic inflammatory response caused by a microbial infection. In the US, sepsis causes ~ 215,000 deaths annually and a healthcare burden of ~ $17 billion. As many as 50% of septic patients develop acute kidney injury (AKI) and this increases mortality from 25% to 75%. Currently, there are no effective therapies to treat sepsis and clinicians must rely only on supportive care usually initiated after the presence of symptoms. Our laboratories recently reported that renal microcirculatory failure and renal mitochondrial superoxide (O2?-) generation occur in the mouse by 4h after induction of sepsis, and these events precede the decline in renal function. Importantly, agents that scavenge oxidants allowed the microcirculation to recover and prevented renal injury. Now we have data showing that activities in the kidney of the major mitochondrial O2?- scavenger, manganese superoxide dismutase (MnSOD) is decreased ~50% by 4h post sepsis and mitochondrial complex II/III is decreased ~30% at 6h. Also, sepsis induced mitochondrial damage stimulates mitophagy (safe removal of mitochondria);however, mitochondrial biogenesis (mitogenesis) is impaired. Based on these data, we hypothesize that during sepsis increased mitochondrial superoxide is a result of both the loss of MnSOD activity and reduced Complex II/III activity. The resulting mitochondrial damage triggers mitophagy but excessive superoxide dampens functional mitochondrial biogenesis. Consequently, agents, which reduce mitochondrial superoxide will allow for functional mitogenesis and improve sepsis-induced AKI.
Three Specific Aims using both the in vivo CLP model as well as a primary cell in vitro model will test this hypothesis.
Aim 1 will establish the temporal relationships between MnSOD inactivation and respiratory chain dysfunction (damage phase) to mitophagy and mitogenesis (attempted recovery phase) during sepsis in mice.
Aim 2 will investigate the molecular mechanisms that inactivate renal epithelial MnSOD during sepsis. Finally, studies in Aim 3 will evaluate the therapeutic potential of mitochondria-targeted antioxidants to reduce renal mitochondrial dysfunction and promote repair during sepsis using a clinically relevant dosing paradigm. The proposal is significant and innovative from not just a public health perspective but also from a pharmacological perspective. It will provide the scientific basis for targeting repair, a neglected area of sepsis research and critically important in the kidney because even mild AKI is recognized as a significant risk factor for chronic AKI.

Public Health Relevance

Sepsis is a serious medical condition characterized by a severe systemic inflammatory response caused by a microbial infection. As many as 50% of septic patients develop acute kidney injury (AKI) and this dramatically increases mortality. Currently, there are no effective therapies to treat sepsis and clinicians must rely only on supportive care usually initiated only after the presence of symptoms. We will be evaluating a new approach to therapy, which will protect the energy producing cells in the kidney.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM106419-01A1
Application #
8655261
Study Section
Special Emphasis Panel (ZRG1-SBIB-X (02))
Program Officer
Dunsmore, Sarah
Project Start
2014-02-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$275,196
Indirect Cost
$85,196
Name
University of Arkansas for Medical Sciences
Department
Pharmacology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Sims, C R; MacMillan-Crow, L A; Mayeux, P R (2014) Targeting mitochondrial oxidants may facilitate recovery of renal function during infant sepsis. Clin Pharmacol Ther 96:662-4
Patil, Naeem K; Parajuli, Nirmala; MacMillan-Crow, Lee Ann et al. (2014) Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury. Am J Physiol Renal Physiol 306:F734-43