scholarly journals Acute Kidney Injury and Organ Dysfunction: What Is the Role of Uremic Toxins?

Toxins ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 551
Author(s):  
Jesús Iván Lara-Prado ◽  
Fabiola Pazos-Pérez ◽  
Carlos Enrique Méndez-Landa ◽  
Dulce Paola Grajales-García ◽  
José Alfredo Feria-Ramírez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Organ Dysfunction ◽  
Kidney Injury ◽  
Uremic Toxins ◽  
Oxygen Species ◽  
Capillary Leakage ◽  
Abrupt Increase ◽  
Epithelial Injury

Acute kidney injury (AKI), defined as an abrupt increase in serum creatinine, a reduced urinary output, or both, is experiencing considerable evolution in terms of our understanding of the pathophysiological mechanisms and its impact on other organs. Oxidative stress and reactive oxygen species (ROS) are main contributors to organ dysfunction in AKI, but they are not alone. The precise mechanisms behind multi-organ dysfunction are not yet fully accounted for. The building up of uremic toxins specific to AKI might be a plausible explanation for these disturbances. However, controversies have arisen around their effects in organs other than the kidney, because animal models usually depict AKI as a kidney-specific injury. Meanwhile, humans present AKI frequently in association with multi-organ failure (MOF). Until now, medium-molecular-weight molecules, such as inflammatory cytokines, have been proven to play a role in endothelial and epithelial injury, leading to increased permeability and capillary leakage, mainly in pulmonary and intestinal tissues.

scholarly journals CO-Releasing Molecule-2 Prevents Acute Kidney Injury through Suppression of ROS-Fyn-ER Stress Signaling in Mouse Model

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Md Jamal Uddin ◽  
Jeewon Jeong ◽  
Eun Seon Pak ◽  
Hunjoo Ha
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Er Stress ◽  
Stress Responses ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Oxygen Species ◽  
Chronic Kidney Diseases ◽  
Tubular Cells ◽  
Cellular Apoptosis

Acute kidney injury (AKI) most commonly appears in critically ill patients in hospitals. AKI is characterized as a quick deterioration of kidney function and has recently been identified to be tightly interlinked with chronic kidney diseases. The emerging major mediators of AKI include oxidative stress and endoplasmic reticulum (ER) stress. Carbon monoxide (CO) attenuates oxidative stress and ER stress in various cells, while Fyn, a member of the Src kinase family, is activated by oxidative stress and contributes to ER stress in skeletal muscle. Considering these, the objective of the current research was to determine (i) the involvement of Fyn in ER stress-mediated AKI and (ii) the effect of CO-releasing molecule-2 (CORM2) on reactive oxygen species- (ROS-) Fyn-ER stress-mediated AKI. Pretreatment with CORM2 (30 mg/kg) efficiently inhibited LPS (30 mg/kg)-induced oxidative stress, inflammation, and cellular apoptosis during AKI in C57BL/6J mice. Also, CORM2 efficiently suppressed the activation of Fyn and ER stress in AKI mice. Consistently, pretreatment with CORM2 inhibited oxidative stress, Fyn activation, ER stress, inflammation, and apoptosis in LPS- or H2O2-stimulated proximal epithelial tubular cells. Fyn inhibition using siRNA or an inhibitor (PP2) significantly attenuated ER stress responses in the cells. These data suggest that CORM2 may become a potential treatment option against ROS-Fyn-ER stress-mediated AKI.

P0525ROLE OF NADPH OXIDASE 4 IN ACUTE KIDNEY INJURY ASSOCIATED TO MASSIVE INTRAVASCULAR HEMOLYSIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Cristina García Caballero ◽  
Melania Guerrero Hue ◽  
Alejandra Palomino Antolín ◽  
Matilde Cabanillas ◽  
Cristina Vazquez Carballo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Renal Damage ◽  
Kidney Injury ◽  
Tubular Injury ◽  
Wild Type ◽  
Intravascular Hemolysis ◽  
Nadph Oxidase 4

Abstract Background and Aims Massive intravascular hemolysis is a common condition of several pathologies. It is associated with acute kidney injury (AKI) and progressive impairment of renal function. In this context, free hemoglobin (Hb) can exert harmful effects by accumulating in the kidney, where induces oxidative stress and it becomes cytotoxic. NADPH oxidase 4 (Nox4) is the principal source of reactive oxygen species (ROS) in the kidney. Nox4 is mostly expressed in proximal tubular cells with lower levels in glomerulus. The role of Nox4 in renal damage is not clear, with studies reporting beneficial or deleterious actions depending of the environmental conditions. For that reason we aimed to investigate the role of Nox4 in massive intravascular hemolysis-associated AKI. Method To study the role of Nox4 in AKI caused by massive intravascular hemolysis, we performed an experimental model of intravascular hemolysis by intraperitoneal injection of phenylhydrazine (200 mg/kg) in wild type (Nox4+/+) and Nox4 knockout mice (Nox4-/-). Mice were sacrificed 24 and 72 hours after intravascular hemolysis induction. We collected serum, urine and tissues sample. We analyzed renal function, oxidative stress, cell death and inflammation in these samples. In other experiments, wild type mice were treated with GKT137831 (10mg/kg/day), a potent Nox4 and Nox1 inhibitor, and mice were sacrificed 72h after induction of hemolysis. We also performed in vitro experiments in murine tubular epithelial cells (MCT) and murine podocytes cells to investigate the regulation of Nox4 in Hb-stimulated cells treated or not with GKT137831. Results Induction of intravascular hemolysis in Nox4+/+ mice increased creatinine and BUN levels and enhanced the expression of tubular injury markers, such as NGAL. These pathological effects were reduced in Nox4 knockout mice. Then, we analyzed oxidative stress in our experimental model thought determination of HO-1, ferritin, GSH and lipid peroxidation levels. All of these oxidative markers were reduced in Nox4-/- mice with intravascular hemolysis as compared with Nox4+/+ mice. We also observed that inflammatory markers such as IL-6, cell death and podocytes injury markers were reduced in Nox4-/- mice than in wild type mice, specially 72 hours after phenylhydrazine injection. In line with these results, GKT137831 administration ameliorated intravascular hemolysis-associated renal function impairment. Moreover, oxidative stress, tubular injury markers and podocyte injury were reduced in hemolytic mice treated with GKT137831. GKT137831 also reduced Hb- and heme-mediated oxidative stress in MCT and podocytes. Conclusion Our results show the important role of Nox4 in renal injury associated to massive intravascular hemolysis. Moreover, the inhibition of Nox4 may be a potential therapeutic target to prevent renal damage associated to Hb accumulation. These findings provide new insights into novel aspects of Hb-toxicity and may have important pathogenic and therapeutic implications for intravascular hemolysis related diseases

scholarly journals The Links between Microbiome and Uremic Toxins in Acute Kidney Injury: Beyond Gut Feeling—A Systematic Review

Toxins ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 788
Author(s):  
Alicja Rydzewska-Rosołowska ◽  
Natalia Sroka ◽  
Katarzyna Kakareko ◽  
Mariusz Rosołowski ◽  
Edyta Zbroch ◽  
...  
Keyword(s):  
Systematic Review ◽  
Acute Kidney Injury ◽  
Targeted Therapy ◽  
Experimental Studies ◽  
Kidney Injury ◽  
Uremic Toxins ◽  
Cochrane Library ◽  
Microbiota Composition ◽  
Ongoing Trial

The last years have brought an abundance of data on the existence of a gut-kidney axis and the importance of microbiome in kidney injury. Data on kidney-gut crosstalk suggest the possibility that microbiota alter renal inflammation; we therefore aimed to answer questions about the role of microbiome and gut-derived toxins in acute kidney injury. PubMed and Cochrane Library were searched from inception to October 10, 2020 for relevant studies with an additional search performed on ClinicalTrials.gov. We identified 33 eligible articles and one ongoing trial (21 original studies and 12 reviews/commentaries), which were included in this systematic review. Experimental studies prove the existence of a kidney-gut axis, focusing on the role of gut-derived uremic toxins and providing concepts that modification of the microbiota composition may result in better AKI outcomes. Small interventional studies in animal models and in humans show promising results, therefore, microbiome-targeted therapy for AKI treatment might be a promising possibility.

scholarly journals Targeting Oxidative Stress in Septic Acute Kidney Injury: From Theory to Practice

2021 ◽  
Vol 10 (17) ◽  
pp. 3798
Author(s):  
Connie P. C. Ow ◽  
Anton Trask-Marino ◽  
Ashenafi H. Betrie ◽  
Roger G. Evans ◽  
Clive N. May ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Reactive Nitrogen Species ◽  
Kidney Injury ◽  
Oxygen Species ◽  
Clinical Sepsis ◽  
Human Sepsis ◽  
Theory To Practice ◽  
Septic Acute Kidney Injury ◽  
Pleiotropic Actions

Sepsis is the leading cause of acute kidney injury (AKI) and leads to increased morbidity and mortality in intensive care units. Current treatments for septic AKI are largely supportive and are not targeted towards its pathophysiology. Sepsis is commonly characterized by systemic inflammation and increased production of reactive oxygen species (ROS), particularly superoxide. Concomitantly released nitric oxide (NO) then reacts with superoxide, leading to the formation of reactive nitrogen species (RNS), predominantly peroxynitrite. Sepsis-induced ROS and RNS can reduce the bioavailability of NO, mediating renal microcirculatory abnormalities, localized tissue hypoxia and mitochondrial dysfunction, thereby initiating a propagating cycle of cellular injury culminating in AKI. In this review, we discuss the various sources of ROS during sepsis and their pathophysiological interactions with the immune system, microcirculation and mitochondria that can lead to the development of AKI. We also discuss the therapeutic utility of N-acetylcysteine and potential reasons for its efficacy in animal models of sepsis, and its inefficacy in ameliorating oxidative stress-induced organ dysfunction in human sepsis. Finally, we review the pre-clinical studies examining the antioxidant and pleiotropic actions of vitamin C that may be of benefit for mitigating septic AKI, including future implications for clinical sepsis.

scholarly journals The Suppression of Pin1-Alleviated Oxidative Stress through the p38 MAPK Pathway in Ischemia- and Reperfusion-Induced Acute Kidney Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Xiaojie Zhao ◽  
Dan Wang ◽  
Shanshan Wan ◽  
Xiuheng Liu ◽  
Wei Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Kidney Injury ◽  
Ischemia And Reperfusion ◽  
P38 Mapk Pathway

Background. Pin1, as the peptidyl-prolyl isomerase, plays a vital role in cellular processes. However, whether it has a regulatory effect on renal ischemia and reperfusion (I/R) injury still remains unknown. Methods. The hypoxia/reoxygenation (H/R) model in human kidney (HK-2) cells and the I/R model in rats were assessed to investigate the role of Pin1 on I/R-induced acute kidney injury. Male Sprague-Dawley rats were used to establish the I/R model for 15, 30, and 45 min ischemia and then 24 h reperfusion, with or without the Pin1 inhibitor, to demonstrate the role of Pin1 in acute kidney injury. HK-2 cells were cultured and experienced the H/R model to identify the molecular mechanisms involved. Results. In this study, we found that Pin1 and oxidative stress were obviously increased after renal I/R. Inhibition of Pin1 with juglone decreased renal structural and functional injuries, as well as oxidative stress. Besides, Pin1 inhibition with the inhibitor, juglone, or the small interfering RNA showed significant reduction on oxidative stress markers caused by the H/R process in vitro. Furthermore, the results indicated that the expression of p38 MAPK was increased during H/R in vitro and Pin1 inhibition could reduce the increased expression of p38 MAPK. Conclusion. Our results illustrated that Pin1 aggravated renal I/R injury via elevating oxidative stress through activation of the p38 MAPK pathway. These findings indicated that Pin1 might become the potential treatment for renal I/R injury.

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