title: Development of oxidative stress in the peritubular capillary microenvironment mediates sepsis-induced renal microcirculatory failure and acute kidney injury.
abstract: Acute kidney injury is a frequent and serious complication of sepsis. To better understand the development of sepsis-induced acute kidney injury, we performed the first time-dependent studies to document changes in renal hemodynamics and oxidant generation in the peritubular microenvironment using the murine cecal ligation and puncture (CLP) model of sepsis. CLP caused an increase in renal capillary permeability at 2 hours, followed by decreases in mean arterial pressure, renal blood flow (RBF), and renal capillary perfusion at 4 hours, which were sustained through 18 hours. The decline in hemodynamic parameters was associated with hypoxia and oxidant generation in the peritubular microenvironment and a decrease in glomerular filtration rate. The role of oxidants was assessed using the superoxide dismutase mimetic/peroxynitrite scavenger MnTMPyP [Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin]. At 10 mg/kg administered 6 hours after CLP, MnTMPyP did not alter blood pressure, but blocked superoxide and peroxynitrite generation, reversed the decline in RBF, capillary perfusion, and glomerular filtration rate, preserved tubular architecture, and increased 48-hour survival. However, MnTMPyP administered at CLP did not prevent capillary permeability or the decrease in RBF and capillary perfusion, which suggests that these early events are not mediated by oxidants. These data demonstrate that renal hemodynamic changes occur early after sepsis and that targeting the later oxidant generation can break the cycle of injury and enable the microcirculation and renal function to recover.
authors: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors: Zhen
authors: Z
authors: Wang
authors: Joseph H
authors: JH
authors: Holthoff
authors: Kathryn A
authors: KA
authors: Seely
authors: Elina
authors: E
authors: Pathak
authors: Horace J
authors: HJ
authors: Spencer
authors: Neriman
authors: N
authors: Gokden
authors: Philip R
authors: PR
authors: Mayeux
mesh_terms: D058186:Acute Kidney Injury / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002196:Capillaries / Q000502:physiology; D002199:Capillary Permeability / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D060833:Cellular Microenvironment / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000502:physiology; D006339:Heart Rate / Q000502:physiology; D008026:Ligation; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012079:Renal Circulation / Q000502:physiology; D018805:Sepsis / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D009566:Nitrates; D009573:Nitrites; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase