Abstract
Induced and frequently unwanted alterations in the mitochondrial structure and functions are a key component of the pathological cascade in many kidney pathologies, including those associated with acute damage. One of the principal pathogenic elements causing mitochondrial dysfunction in Acute Kidney Injury (AKI) is oxidative stress. After ischemia and nephrotoxic action of drugs, sepsis and systemic inflammation are the most frequent causes of AKI. As the kidney suffers from oxidative stress during sepsis, one of the most promising approaches to alleviate such damaging consequences is the use of antioxidants. Considering administration of lipopolysaccharide (LPS) as a model of sepsis, we demonstrate that the mitochondria of neonatal renal tissue are severely affected by LPS-induced AKI, with pathological ultrastructural changes observed in both the mitochondria of the renal tubular epithelium and the vascular endothelium. Upon mitochondrial damage, we evaluated the effect of the mitochondria-targeted antioxidant plastoquinol decylrhodamine 19 (SkQR1) on the development of acute renal failure in newborn rats associated with systemic inflammation induced by the administration of LPS. We found that SkQR1 administration 3 h before LPS led to decreased urinal expression of the AKI marker neutrophil gelatinase-associated lipocalin 2 (NGAL), in addition to a decrease in urea and creatinine levels in the blood. Additionally, an observed impairment of proliferative activity in the neonatal kidney caused by LPS treatment was also prevented by the treatment of rat pups with SkQR1. Thus, one of the key events for renal tissue damage in neonatal sepsis is an alteration in the structure and function of the mitochondria and the mitochondria-targeted antioxidant SkQR1 is an effective nephroprotective agent, which protects the neonatal kidney from sepsis-induced AKI.
Highlights
Sepsis is a complex syndrome, arising from bacterial invasion and the development of systemic inflammation, which eventually leads to multi-organ failure and, often, to death [1]; even with treatments using antibiotics
These approaches can be quite universal in their use, for the treatment of neonatal sepsis, since they counteract unwanted activation of the pathogenic redox cycle of reactive oxygen species (ROS) production stemming from the mitochondrial respiratory chain, which may be subject to amplification; potentially creating a pathological damaging signal
Membranes were blocked for 1 h at 25 ◦ C in phosphate-buffered saline (PBS) with 5% non-fat dry milk and 0.05% Tween-20, incubated with primary antibodies against neutrophil gelatinase-associated lipocalin 2 (NGAL), kidney injury molecule-1 (KIM-1) (Abcam, Cambridge, UK), and Proliferative cell nuclear antigen (PCNA) (Abcam, UK) at a dilution of 1:1000 in PBS/BSA/Tween-20 and, with secondary antibodies conjugated with horseradish peroxidase at a dilution of 1:10,000 in PBS/Tween-20
Summary
Sepsis is a complex syndrome, arising from bacterial invasion and the development of systemic inflammation, which eventually leads to multi-organ failure and, often, to death [1]; even with treatments using antibiotics. For the treatment of sepsis, the proposed approaches are aimed at extinguishing the mitochondrial-specific oxidative burst, primarily by using mitochondria-targeted antioxidants These approaches can be quite universal in their use, for the treatment of neonatal sepsis, since they counteract unwanted activation of the pathogenic redox cycle of ROS production stemming from the mitochondrial respiratory chain, which may be subject to amplification; potentially creating a pathological damaging signal. In this cascade, mitochondria, being a primary source of signaling ROS, can produce ROS in an amount exceeding normal physiological levels, leading to greater mitochondrial dysfunction through a self-amplifying ROS signal, which can have consequences beyond the mitochondrion [22]. As a model of sepsis, we induced renal failure by LPS to assess the nephroprotective action of the mitochondria-targeted compound plastoquinone decylrhodamine 19 (SkQR1), which demonstrated remarkable antioxidative and protective properties in a model of renal ischemia and myoglobinuria [24]
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