Molecular Interactions Between Reactive Oxygen Species and Autophagy in Kidney Disease

Effects of vitamin C infusion and vitamin E-coated membrane on hemodialysis-induced oxidative stress

It is well appreciated that reactive oxygen species (ROS) are deleterious to mammals, including humans, especially when generated in abnormally large quantities from cellular metabolism. Whereas the mechanisms leading to the production of ROS are rather well delineated, the mechanisms underlying tissue susceptibility or tolerance to oxidant stress remain elusive. Through an experimental selection over many generations, we have previously generated Drosophila melanogaster flies that tolerate tremendous oxidant stress and have shown that the family of antimicrobial peptides (AMPs) is over-represented in these tolerant flies. Furthermore, we have also demonstrated that overexpression of even one AMP at a time (e.g. Diptericin) allows wild-type flies to survive much better in hyperoxia. In this study, we used a number of experimental approaches to investigate the potential mechanisms underlying hyperoxia tolerance in flies with AMP overexpression. We demonstrate that flies with Diptericin overexpression resist oxidative stress by increasing antioxidant enzyme activities and preventing an increase in ROS levels after hyperoxia. Depleting the GSH pool using buthionine sulfoximine limits fly survival, thus confirming that enhanced survival observed in these flies is related to improved redox homeostasis. We conclude that 1) AMPs play an important role in tolerance to oxidant stress, 2) overexpression of Diptericin changes the cellular redox balance between oxidant and antioxidant, and 3) this change in redox balance plays an important role in survival in hyperoxia.

SKN-1/Nrf, A New Unfolded Protein Response Factor?

The prevalence of renal diseases including acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing worldwide. However, the pathogenesis of most renal diseases is still unclear and effective treatments are still lacking. DNA damage and the related DNA damage response (DDR) have been confirmed as common pathogenesis of acute kidney injury and chronic kidney disease. Reactive oxygen species (ROS) induced DNA damage is one of the most common types of DNA damage involved in the pathogenesis of acute kidney injury and chronic kidney disease. In recent years, several developments have been made in the field of DNA damage. Herein, we review the roles and developments of DNA damage and DNA damage response in renal tubular epithelial cell injury in acute kidney injury and chronic kidney disease. In this review, we conclude that focusing on DNA damage and DNA damage response may provide valuable diagnostic biomarkers and treatment strategies for renal diseases including acute kidney injury and chronic kidney disease.

Reactive oxygen species generation by human spermatozoa: a continuing enigma.

Angiotensin-converting enzyme (ACE) inhibitors are potent members of the arsenal to treat chronic kidney disease (CKD). By reducing blood pressure (BP) and disproportionately decreasing intraglomerular pressure, this class of drugs also reduces proteinuria and slows progression of CKD (1,2). Given the high prevalence of cardiovascular disease in this population, it is noteworthy that ACE inhibitors also decrease the incidence of stroke, myocardial infarction (MI), and cardiovascular mortality in patients who are at high cardiovascular risk (3). More recently, data reporting similar benefits of angiotensin receptor blockers (ARB) support their use in the treatment of CKD as well, especially in individuals with type 2 diabetes (4). Furthermore, one sizable study suggested that the combination of an ACE inhibitor and ARB may be more effective than either agent alone (5). Parving and colleagues (6) called attention to the effects of high-dose ARB therapy, up to three times the recommended dose, as an additional means of effectively interrupting the renin-angiotensin-aldosterone system (RAAS). By logical extension, further blockade of the RAAS by direct antagonism of aldosterone also may prove beneficial. Indeed, aldosterone seems to be a potent effector of renal injury (7–9). In the rare cases of primary aldosteronism and its functional analogue, the even more rare Liddle’s syndrome, the observed renal injury probably is independent of the more proximal elements of the RAAS (10,11). Animal models provide an expeditious tool for assessing pathophysiologic change and the efficacy of intervention. The classic model of primary aldosteronism, the mineralocorticoid–nephrectomy–high-salt model of hypertension, develops systemic and glomerular capillary hypertension and sustains renal damage (12). In the remnant kidney model of CKD, ACE inhibitors and ARB attenuate renal injury (13). However, this protection, which is associated with suppression of aldosterone secretion, is abrogated by exogenous aldosterone infusion with return of …

Despite the identification of several of the cellular mechanisms thought to underlie the development of acute kidney injury (AKI), the pathophysiology of AKI is still poorly understood. It is clear, however, that instead of a single mechanism being responsible for its etiology, AKI is associated with an entire orchestra of failing cellular mechanisms. Renal microcirculation is the physiological compartment where these mechanisms come together and exert their integrated deleterious action. Therefore, the study of renal microcirculation and the identification of the determinants of its function in models of AKI can be expected to provide insight into the pathogenesis and resolution of AKI. A major determinant of adequate organ function is the adequate oxygen (O(2)) supply at the microcirculatory level and utilization at mitochondrial levels for ATP production needed for performing organ function. The highly complex architecture of the renal microvasculature, the need to meet a high energy demand and the borderline hypoxemic nature of the kidney makes it an organ that is highly vulnerable to injury. Under normal, steady-state conditions, the oxygen supply to the renal tissues is well regulated and utilized not only for mitochondrial production of ATP (mainly for Na reabsorption), but also for the production of nitric oxide and the reactive oxygen species needed for physiological control of renal function. Under pathological conditions, such as inflammation, shock or sepsis, however, the renal microcirculation becomes compromised, which results in a disruption of the homeostasis of nitric oxide, reactive oxygen species, and oxygen supply and utilization. This imbalance results in these compounds exerting pathogenic effects, such as hypoxemia and oxidative stress, resulting in further deterioration of renal microcirculatory function. Our hypothesis is that this sequence of events underlies the development of AKI and that integrated therapeutic modalities targeting these pathogenic mechanisms will be effective therapeutic strategies in the clinical environment.

Skin, our first interface to the external environment, is subjected to oxidative stress caused by a variety of factors such as solar ultraviolet, infrared and visible light, environmental pollution, including ozone and particulate matters, and psychological stress. Excessive reactive species, including reactive oxygen species and reactive nitrogen species, exacerbate skin pigmentation and aging, which further lead to skin tone unevenness, pigmentary disorder, skin roughness and wrinkles. Besides these, skin microbiota are also a very important factor ensuring the proper functions of skin. While environmental factors such as UV and pollutants impact skin microbiota compositions, skin dysbiosis results in various skin conditions. In this review, we summarize the generation of oxidative stress from exogenous and endogenous sources. We further introduce current knowledge on the possible roles of oxidative stress in skin pigmentation and aging, specifically with emphasis on oxidative stress and skin pigmentation. Meanwhile, we summarize the science and rationale of using three well-known antioxidants, namely vitamin C, resveratrol and ferulic acid, in the treatment of hyperpigmentation. Finally, we discuss the strategy for preventing oxidative stress-induced skin pigmentation and aging.

Mitochondria play a major role in energy metabolism, particularly in cell respiration, cellular metabolism, and signal transduction, and are also involved in other processes, such as cell signaling, cell cycle control, cell growth, differentiation and apoptosis. Programmed cell death is associated with the production of reactive oxygen species (ROS) and a concomitant decrease in antioxidant capacity, which, in turn, determines the aging of living organisms and organs and thus also seeds. During the aging process, cell redox homeostasis is disrupted, and these changes decrease the viability of stored seeds. Mitochondrial peroxiredoxin-IIF (PRXIIF), a thiol peroxidase, has a significant role in protecting the cell and sensing oxidative stress that occurs during the disturbance of redox homeostasis. Thioredoxins (TRXs), which function as redox transmitters and switch protein function in mitochondria, can regulate respiratory metabolism. TRXs serve as electron donors to PRXIIF, as shown in Arabidopsis. In contrast, sulfiredoxin (SRX) can regenerate mitochondrial PRXIIF once hyperoxidized to sulfinic acid. To protect against oxidative stress, another type of thiol peroxidases, glutathione peroxidase-like protein (GPXL), is important and receives electrons from the TRX system. They remove peroxides produced in the mitochondrial matrix. However, the TRX/PRX and TRX/GPXL systems are not well understood in mitochondria. Knowledge of both systems is important because these systems play an important role in stress sensing, response and acclimation, including redox imbalance and generation of ROS and reactive nitrogen species (RNS). The TRX/PRX and TRX/GPXL systems are important for maintaining cellular ROS homeostasis and maintaining redox homeostasis under stress conditions. This minireview focuses on the functions of PRXIIF discovered in plant cells approximately 20 years ago and addresses the question of how PRXIIF affects seed viability maintenance and aging. Increasing evidence suggests that the mitochondrial PRXIIF plays a major role in metabolic processes in seeds, which was not previously known.

Background: Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder encompassing Crohn’s disease (CD) and ulcerative colitis (UC). Increasing evidence suggests that impaired intestinal immune regulation in IBD is closely linked to an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, resulting in oxidative stress. Excessive ROS generation and lipid peroxidation contribute to mucosal injury, activation of inflammatory signaling pathways, and disease progression. Objective: The aim of this study was to evaluate the role of oxidative stress markers—ROS production and malondialdehyde (MDA)—measured in peripheral blood, as well as antioxidant status, in relation to disease course and treatment in patients with IBD. Materials and Methods: A cross-sectional study was conducted including 21 children and young adults with IBD (aged 14–25 years; mean age ~17.1 years) and 22 age-matched healthy controls (mean age ~17.6 years). Among the IBD cohort, 9 patients (42%) were male and 12 (58%) were female; 7 patients were diagnosed with CD and 14 with UC. All IBD patients underwent histological assessment. Results: Increased ROS production was positively correlated with elevated MDA levels, indicating enhanced lipid peroxidation and oxidative stress in patients with IBD. Conclusions: The therapeutic efficacy of anti-inflammatory treatments, including azathioprine, corticosteroids, mesalazine, and biological agents, may be partly attributed to their capacity to reduce ROS production and lipid peroxidation in intestinal mucosal cells, thereby promoting mucosal healing in patients with IBD.

BackgroundDuring the production of L-arginine through high dissolved oxygen and nitrogen supply fermentation, the industrial workhorse Corynebacterium glutamicum is exposed to oxidative stress. This generates reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are harmful to the bacteria. To address the issue and to maintain redox homeostasis during fermentation, the flavohaemoprotein (Hmp) was employed.ResultsThe results showed that the overexpression of Hmp led to a decrease in ROS and RNS content by 9.4% and 22.7%, respectively, and improved the survivability of strains. When the strains were treated with H2O2 and NaNO2, the RT-qPCR analysis indicated an up-regulation of ammonium absorption and transporter genes amtB and glnD. Conversely, the deletion of hmp gives rise to the up-regulation of eight oxidative stress-related genes. These findings suggested that hmp is associated with oxidative stress and intracellular nitrogen metabolism genes. Finally, we released the inhibitory effect of ArnR on hmp. The Cc-ΔarnR-hmp strain produced 48.4 g/L L-arginine during batch-feeding fermentation, 34.3% higher than the original strain.ConclusionsThis report revealed the influence of dissolved oxygen and nitrogen concentration on reactive species of Corynebacterium glutamicum and the role of the Hmp in coping with oxidative stress. The Hmp first demonstrates related to redox homeostasis and nitrite metabolism, providing a feasible strategy for improving the robustness of strains.

Biomarkers for metabolic drug activation : towards an integrated risk assessment for drug-induced liver injury (DILI)

Chapter 5 Pathogenesis of Renal Diseases: Renal Cell Response to Injury

Background : Atrial fibrillation (AF) has been shown to be associated with increased oxidative stress mediated by reactive oxygen species (ROS). Previous studies have proposed that there is a link between oxidative stress and AF, and thus oxidative stress may contribute to the pathological consequences of AF such as thrombosis, inflammation, and atrial tissue remodeling. Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) which is a product of deoxyribonucleic acid (DNA) damage by ROS has become to be regarded as a putative biomarker of oxidative DNA damage. Also, biopyrrins which are oxdative metabolites of bilirubin (an important scavenger of ROS) are considered as the potential marker of oxdative stress. In the present study, we assessed serial changes in oxidative stress in patients with AF after cardioversion by measuring urinary 8-OHdG and urinary biopyrrin excretion. Methods and Results : The study subjects consisted of 15 patients with persistent or chronic AF, who underwent electrical or pharmacological cardioversion. We measured urinary 8-OHdG and biopyrrin levels obtained before cardioversion and 24 hours after cardioversion using enzyme-linked immunosorbent assay. There was no significant difference in the biopyrrin/creatinine levels before and 24 hours after cardioversion (3.2±2.6 vs. 3.3±2.4 mU/mg, P=NS). However, 8-OHdG/creatinine levels decreased significantly 24 hours after cardioversion (18.4±9.1 vs. 14.7±8.5 ng/mg, P=0.0012). There was no significant correlation between urinary 8-OHdG/creatinine and biopyrrin/creatinine levels. This discrepancy may be related to the difference in the time course between urinary 8-OHdG/creatinine and biopyrrin/creatinine levels. Thus, measurement of 8-OHdG/creatinine levels seemed to be a more useful marker which reflects the oxidative stress than biopyrrin/creatinine levels at the time 24 hours after cardioversion. Conclusions : These findings suggest that the restoration of sinus rhythm by cardioversion decreases oxidative DNA damage in AF patients, and urinary 8-OHdG may be useful for the estimation of oxidative stress in AF patients. The increase of oxidative stress may play an important role in the pathogenesis of AF, and persist AF and result in the perpetuation of AF.

Albumin-bound fatty acids induce mitochondrial oxidant stress and impair antioxidant responses in proximal tubular cells