Difference between revisions of "Patil 2014 Am J Physiol Renal Physiol"
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{{Publication | {{Publication | ||
|title=Patil NK, Parajuli N, Macmillan-Crow LA, Mayeux PR (2014) Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria targeted antioxidant mitigates injury. Am J Physiol Renal Physiol | |title=Patil NK, Parajuli N, Macmillan-Crow LA, Mayeux PR (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. | ||
|info=[http://www.ncbi.nlm.nih.gov/pubmed/24500690 PMID: 24500690] | |info=[http://www.ncbi.nlm.nih.gov/pubmed/24500690 PMID:24500690] | ||
|authors=Patil NK, Parajuli N, Macmillan-Crow LA, Mayeux PR | |authors=Patil NK, Parajuli N, Macmillan-Crow LA, Mayeux PR | ||
|year=2014 | |year=2014 | ||
|journal=Am J Physiol Renal Physiol | |journal=Am J Physiol Renal Physiol | ||
|abstract=Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 hours after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 hours. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 hours post CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 hours. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-hour survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI. | |abstract=Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 hours after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 hours. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 hours post CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 hours. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-hour survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI. | ||
|keywords=Sepsis, Kidney, Mitochondria, Oxidative stress, Mitochondrial antioxidant | |||
|mipnetlab=US AR Little Rock MacMillan-Crow LA | |||
}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration | |area=Respiration | ||
|organism=Mouse | |||
|tissues=Kidney | |||
|preparations=Permeabilized tissue | |||
|couplingstates=LEAK, OXPHOS | |||
|pathways=N, S, CIV | |||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
}} | }} |
Latest revision as of 08:42, 8 November 2016
Patil NK, Parajuli N, Macmillan-Crow LA, Mayeux PR (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. |
Patil NK, Parajuli N, Macmillan-Crow LA, Mayeux PR (2014) Am J Physiol Renal Physiol
Abstract: Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 hours after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 hours. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 hours post CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 hours. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-hour survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI. β’ Keywords: Sepsis, Kidney, Mitochondria, Oxidative stress, Mitochondrial antioxidant
β’ O2k-Network Lab: US AR Little Rock MacMillan-Crow LA
Labels: MiParea: Respiration
Organism: Mouse
Tissue;cell: Kidney
Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS
Pathway: N, S, CIV
HRR: Oxygraph-2k