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.

The Beneficial Effects of Agomelatine in Experimental Model of Sepsis Related Acute Kidney Injury

“…[31] It has been determined that oxidative stress plays an important role in sepsis-related AKI. [32] The results of the present study support this conclusion. MDA, the end-product of lipid peroxidation, was higher in the sepsis group than in the normal and sham groups.…”

IGF-1 may predict the severity and outcome of patients with sepsis and be associated with microRNA-1 level changes

“…In sepsis, excessive reactive oxygen species (ROS) generated from oxidative stress is the main pathogenic mechanism for the occurrence of MODS in patients with sepsis, which is influential of the patient's disease condition and prognosis (16,17) The mechanism of this process can simply described as follows: When sepsis occurs, lipopolysaccharide binding proteins on the surfaces of neutrophils and mononuclear macrophages bind with endotoxins, which activates the intracellular xanthine oxidase to release a large number of electrons and produce excess ROS, which may lead to oxidative stress status (5,18,19). Excess ROS can cause damage to mitochondria and induce apoptosis, and more importantly, activate the inflammatory signaling pathways, and activate complement, resulting in a loss of control of inflammatory reactions and damage to multiple organs (20,21).…”

Renal Hemodynamics in AKI

“…21,26 Similarly, rodent models of acute endotoxemia suggest that cortical peritubular capillaries are among the first renal structures injured. [27][28][29][30] Interestingly, despite an apparent full recovery of renal function at 48 hours, functional capillary density recovered only partially. 27 Moreover, areas of compromised cortical microvascular perfusion have been shown to correlate with renal tubular cell stress in corresponding regions, suggesting important links between altered peritubular microcirculation and epithelial cell dysfunction.…”

“…Oxidative stress-mediated cellular injury has been implicated in the pathogenesis of AKI as a central element of the network of danger response, affecting both endothelial and epithelial functions as well as cellular energetics. 33 Therapeutic interventions aimed at maintaining the homeostatic balance between oxygen radicals, nitric oxide, and oxygen have been shown to be effective in several studies in rodent models of septic AKI [27][28][29][30][31] and ischemia-reperfusion injury 52 as well as in large animal models of septic AKI. 53,54 The lack of effective inducible nitric oxide synthase inhibitors for clinical use can be considered an important area for research.…”