scholarly journals Suppressed Hepatic Production of Indoxyl Sulfate Attenuates Cisplatin-Induced Acute Kidney Injury in Sulfotransferase 1a1-Deficient Mice

2021 ◽  
Vol 22 (4) ◽  
pp. 1764
Author(s):  
Nozomi Yabuuchi ◽  
Huixian Hou ◽  
Nao Gunda ◽  
Yuki Narita ◽  
Hirofumi Jono ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Indoxyl Sulfate ◽  
Uremic Toxin ◽  
Endogenous Factors ◽  
Sulfotransferase 1A1 ◽  
Aryl Hydrocarbon ◽  
Nadph Oxidase 4 ◽  
Antioxidant Stress

Endogenous factors involved in the progression of cisplatin nephropathy remain undetermined. Here, we demonstrate the toxico-pathological roles of indoxyl sulfate (IS), a sulfate-conjugated uremic toxin, and sulfotransferase 1A1 (SULT1A1), an enzyme involved in its synthesis, in cisplatin-induced acute kidney injury using Sult1a1-deficient (Sult1a1-/- KO) mice. With cisplatin administration, severe kidney dysfunction, tissue damage, and apoptosis were attenuated in Sult1a1-/- (KO) mice. Aryl hydrocarbon receptor (AhR) expression was increased by treatment with cisplatin in mouse kidney tissue. Moreover, the downregulation of antioxidant stress enzymes in wild-type (WT) mice was not observed in Sult1a1-/- (KO) mice. To investigate the effect of IS on the reactive oxygen species (ROS) levels, HK-2 cells were treated with cisplatin and IS. The ROS levels were significantly increased compared to cisplatin or IS treatment alone. IS-induced increases in ROS were reversed by downregulation of AhR, xanthine oxidase (XO), and NADPH oxidase 4 (NOX4). These findings suggest that SULT1A1 plays toxico-pathological roles in the progression of cisplatin-induced acute kidney injury, while the IS/AhR/ROS axis brings about oxidative stress.

scholarly journals Hepatic Sulfotransferase as a Nephropreventing Target by Suppression of the Uremic Toxin Indoxyl Sulfate Accumulation in Ischemic Acute Kidney Injury

2014 ◽  
Vol 141 (1) ◽  
pp. 206-217 ◽  
Author(s):  
Hideyuki Saito ◽  
Misato Yoshimura ◽  
Chika Saigo ◽  
Megumi Komori ◽  
Yui Nomura ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Indoxyl Sulfate ◽  
Uremic Toxin ◽  
Ischemic Acute Kidney Injury

scholarly journals Immunopathogenesis of Acute Kidney Injury

2018 ◽  
Vol 46 (8) ◽  
pp. 930-943 ◽  
Author(s):  
Zaher A. Radi
Keyword(s):  
Acute Kidney Injury ◽  
T Cells ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Drug Induced ◽  
Inflammatory Damage ◽  
Anti Inflammatory ◽  
Renal Tubular ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Pathophysiologically, the classification of acute kidney injury (AKI) can be divided into three categories: (1) prerenal, (2) intrinsic, and (3) postrenal. Emerging evidence supports the involvement of renal tubular epithelial cells and the innate and adaptive arms of the immune system in the pathogenesis of intrinsic AKI. Pro-inflammatory damage-associated molecular patterns, pathogen-associated molecular patterns, hypoxia inducible factors, toll-like receptors, complement system, oxidative stress, adhesion molecules, cell death, resident renal dendritic cells, neutrophils, T and B lymphocytes, macrophages, natural killer T cells, cytokines, and secreted chemokines contribute to the immunopathogenesis of AKI. However, other immune cells and pathways such as M2 macrophages, regulatory T cells, progranulin, and autophagy exhibit anti-inflammatory properties and facilitate kidney tissue repair after AKI. Thus, therapies for AKI include agents such as anti-inflammatory (e.g., recombinant alkaline phosphatase), antioxidants (iron chelators), and apoptosis inhibitors. In preclinical toxicity studies, drug-induced kidney injury can be seen after exposure to a nephrotoxicant test article due to immune mechanisms and dysregulation of innate, and/or adaptive cellular immunity. The focus of this review will be on intrinsic AKI, as it relates to the immune and renal systems cross talks focusing on the cellular and pathophysiologic mechanisms of AKI.

scholarly journals Indoxyl Sulfate, a Uremic Endotheliotoxin

Toxins ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 229 ◽  
Author(s):  
Guillaume Lano ◽  
Stéphane Burtey ◽  
Marion Sallée
Keyword(s):  
Cardiovascular Health ◽  
Plasma Concentrations ◽  
Cardiovascular Complications ◽  
Indoxyl Sulfate ◽  
Uremic Toxin ◽  
Prooxidant Effect ◽  
Aryl Hydrocarbon ◽  
Cardiovascular Morbidity And Mortality ◽  
And Control

Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)—derived from tryptophan metabolism—accumulates. IS is involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial dysfunction implicated in cardiovascular morbidity and mortality during CKD. In this review, we describe clinical and experimental evidence for IS endothelial toxicity and focus on the various molecular pathways implicated. In patients with CKD, plasma concentrations of IS correlate with cardiovascular events and mortality, with vascular calcification and atherosclerotic markers. Moreover, IS induces a prothrombotic state and impaired neovascularization. IS reduction by AST-120 reverse these abnormalities. In vitro, IS induces endothelial aryl hydrocarbon receptor (AhR) activation and proinflammatory transcription factors as NF-κB or AP-1. IS has a prooxidant effect with reduction of nitric oxide (NO) bioavailability. Finally, IS alters endothelial cell and endothelial progenitor cell migration, regeneration and control vascular smooth muscle cells proliferation. Reducing IS endothelial toxicity appears to be necessary to improve cardiovascular health in CKD patients.

Acute kidney injury in the cancer patient

2015 ◽  
Author(s):  
Gilbert W. Moeckel ◽  
Veena Manjunath ◽  
Mark A. Perazella
Keyword(s):  
Acute Kidney Injury ◽  
Cancer Patients ◽  
Clinical Presentation ◽  
Kidney Tissue ◽  
Hospital Setting ◽  
Kidney Injury ◽  
Direct Effects ◽  
Significant Morbidity ◽  
Adequate Treatment ◽  
Kidney Lesions

Acute kidney injury in cancer patients is a complicated clinical condition associated with significant morbidity and mortality, especially in the hospital setting. Cancer patients may develop a variety of different kidney lesions that impair not only immediate survival but also limit the adequate treatment of the underlying malignant process. This poses a significant challenge for clinicians.The mechanisms that lead to acute kidney injury in cancer patients are similar to those seen in non-cancer patients. Moreover, significant morbidity is seen in association with chemotherapy, as well as through direct effects of the cancer on the kidney (i.e. obstruction, infiltrate).This chapter reviews the clinical presentation of the most common malignancies that affect the kidney, discusses their pathologic manifestations in kidney tissue, and reviews options for the clinical management of cancer patients with acute kidney injury.

Pathophysiology of Acute Kidney Injury, Repair, and Regeneration

2014 ◽  
Author(s):  
Ching-Wei Tsai ◽  
Sanjeev Noel ◽  
Hamid Rabb
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Critical Role ◽  
Recovery Period ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Phase Cell ◽  
M2 Macrophage ◽  
Renal Stem Cells

Acute kidney injury (AKI), regardless of its aetiology, can elicit persistent or permanent kidney tissue changes that are associated with progression to end-stage renal disease and a greater risk of chronic kidney disease (CKD). In other cases, AKI may result in complete repair and restoration of normal kidney function. The pathophysiological mechanisms of renal injury and repair include vascular, tubular, and inflammatory factors. The initial injury phase is characterized by rarefaction of peritubular vessels and engagement of the immune response via Toll-like receptor binding, activation of macrophages, dendritic cells, natural killer cells, and T and B lymphocytes. During the recovery phase, cell adhesion molecules as well as cytokines and chemokines may be instrumental by directing the migration, differentiation, and proliferation of renal epithelial cells; recent data also suggest a critical role of M2 macrophage and regulatory T cell in the recovery period. Other processes contributing to renal regeneration include renal stem cells and the expression of growth hormones and trophic factors. Subtle deviations in the normal repair process can lead to maladaptive fibrotic kidney disease. Further elucidation of these mechanisms will help discover new therapeutic interventions aimed at limiting the extent of AKI and halting its progression to CKD or ESRD.

COVID-19 aus Sicht des Nephrologen

2020 ◽  
Vol 145 (15) ◽  
pp. 1068-1073
Author(s):  
Martin Kann ◽  
Thomas Benzing
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Transplantation ◽  
Current Knowledge ◽  
Early Stage ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Chronic Hemodialysis ◽  
Initial Presentation ◽  
Proximal Tubular ◽  
Insight Into

AbstractIncreasing insight into the clinical phenotype and mechanisms of SARS-CoV-2 infections and COVID-19 has identified damage of the kidneys as a key player in the course of the disease. This manuscript summarizes the current knowledge on direct viral infection of kidney tissue, proteinuria and acute kidney injury in COVID-19, and management of patients on chronic dialysis as well as after kidney transplantation. Direct infection of podocytes and proximal tubular cells by SARS-CoV-2 has been confirmed and results in proteinuria and hematuria at an early stage of COVID-19. In this context, any kidney affection is a predictor of worse outcomes among COVID-19 patients irrespective of the initial presentation and increases the risk of acute kidney injury. Specific therapies for kidney damage and acute kidney injury within COVID-19 that could be generally recommended are currently lacking. Patients on chronic hemodialysis in particular are at risk for contracting SARS-CoV-2 infections as indicated by outbreaks and super-spreading events in hemodialysis facilities. Immunosuppressive therapy after kidney transplantation needs to be adapted upon diagnosis of COVID-19 depending on the severity of the initial presentation.

Two different melatonin treatment regimens prevent an increase in kidney injury marker-1 induced by carbon tetrachloride in rat kidneys

2019 ◽  
Vol 97 (5) ◽  
pp. 422-428 ◽  
Author(s):  
Milan Potić ◽  
Ivan Ignjatović ◽  
Vanja P. Ničković ◽  
Jovan B. Živković ◽  
Jelena D. Krdžić ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Carbon Tetrachloride ◽  
Morphological Changes ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Specific Marker ◽  
Melatonin Treatment ◽  
Serum Parameters ◽  
Treatment Regimens ◽  
Standard Serum

Acute kidney injury is a frequent disorder that can be mimicked by the application of different nephrotoxic agents, including carbon tetrachloride (CCl4), where kidney injury marker-1 (KIM-1) has been recognized as a highly specific marker. Melatonin is one of the most powerful natural antioxidants and has numerous beneficial properties. We evaluated the nephroprotective potential of 2 melatonin treatment regimens (pre- and post-intoxication) in a CCl4-induced acute kidney injury model based on the standard serum parameters, kidney tissue antioxidative capacity, KIM-1 levels, and kidney tissue morphological changes. The two treatment regimens were found to preserve kidney function, as judged from the evaluated standard serum parameters. Only when administered after the intoxication, melatonin preserved total kidney antioxidant capacity; pre-treatment melatonin only preserved reduced glutathione levels. An increase in tissue KIM-1 level was found to be prevented by both treatment regimens, which correlated with the morphological changes seen in the kidney tissues of animals treated with melatonin and CCl4. The findings of our study are in agreement with the known actions of melatonin in relieving kidney tissue oxidative burden, but also contribute to the understanding of its action by preventing an increase in KIM-1.

scholarly journals Comparison of olive leaf, olive oil, palm oil, and omega-3 oil in acute kidney injury induced by sepsis in rats

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7219 ◽  
Author(s):  
Maria Fátima de Paula Ramos ◽  
Olvania Basso Oliveira ◽  
Alceni do Carmo Morais Monteiro de Barros ◽  
Clara Versolato Razvickas ◽  
Edson de Andrade Pessoa ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Olive Oil ◽  
Palm Oil ◽  
Interleukin 1 ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Therapeutic Interventions ◽  
Natural Food ◽  
Omega 3 ◽  
Olive Leaf

BackgroundHypotension, increased production of reactive oxygen species, and inflammation are all observed in experimental models of sepsis induced by lipopolysaccharide (LPS).PurposeThe aim of this study was to evaluate the effects of an ethanolic extract of Brazilian olive leaf (Ex), Brazilian olive oil (Olv), Ex + Olv (ExOlv), and palm oil (Pal) in comparison to the effects of omega-3 fish oil (Omg) in a rat model of sepsis-induced acute kidney injury.MaterialsWistar rats were divided into seven groups (seven per group), which were either untreated (control) or treated with LPS, LPS + Ex, LPS + ExOlv, LPS + Olv, LPS + Omg, or LPS + Pal.ResultsLower values of creatinine clearance and blood pressure were observed in the LPS-treated group, and these values were not affected by Ex, Olv, ExOlv, Pal, or Omg treatment. Mortality rates were significantly lower in rats exposed to LPS when they were also treated with Ex, ExOlv, Olv, Pal, or Omg. These treatments also decreased oxidative stress and inflammation (Tumor necrosis factor alpha, interleukin-1 beta) and increased interleukin-10 levels and cell proliferation, which were associated with decreased apoptosis in kidney tissue.ConclusionEx and Pal treatments were beneficial in septic rats, since they increased survival rate and did not aggravate inflammation. However, the most effective treatments for septic rats were Olv in comparison to Omg. These natural food substances could enable the development of effective therapeutic interventions to sepsis.

scholarly journals Development of an Immunoassay for the Kidney-Specific Protein myo-Inositol Oxygenase, a Potential Biomarker of Acute Kidney Injury

2014 ◽  
Vol 60 (5) ◽  
pp. 747-757 ◽  
Author(s):  
Joseph P Gaut ◽  
Dan L Crimmins ◽  
Matt F Ohlendorf ◽  
Christina M Lockwood ◽  
Terry A Griest ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Large Scale ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Specific Protein ◽  
Creatinine Concentration ◽  
Potential Biomarker ◽  
Mouse Tissues

Abstract BACKGROUND Acute kidney injury (AKI) affects 45% of critically ill patients, resulting in increased morbidity and mortality. The diagnostic standard, plasma creatinine, is nonspecific and may not increase until days after injury. There is significant need for a renal-specific AKI biomarker detectable early enough that there would be a potential window for therapeutic intervention. In this study, we sought to identify a renal-specific biomarker of AKI. METHODS We analyzed gene expression data from normal mouse tissues to identify kidney-specific genes, one of which was Miox. We generated monoclonal antibodies to recombinant myo-inositol oxygenase (MIOX) and developed an immunoassay to quantify MIOX in plasma. The immunoassay was tested in animals and retrospectively in patients with and without AKI. RESULTS Kidney tissue specificity of MIOX was supported by Western blot. Immunohistochemistry localized MIOX to the proximal renal tubule. Serum MIOX, undetectable at baseline, increased 24 h following AKI in mice. Plasma MIOX was increased in critically ill patients with AKI [mean (SD) 12.4 (4.3) ng/mL, n = 42] compared with patients without AKI [0.5 (0.3) ng/mL, n = 17] and was highest in patients with oliguric AKI [20.2 (7.5) ng/mL, n = 23]. Plasma MIOX increased 54.3 (3.8) h before the increase in creatinine. CONCLUSIONS MIOX is a renal-specific, proximal tubule protein that is increased in serum of animals and plasma of critically ill patients with AKI. MIOX preceded the increases in creatinine concentration by approximately 2 days in human patients. Large-scale studies are warranted to further investigate MIOX as an AKI biomarker.

CREB, NF-κB, and NADPH oxidase coordinately upregulate indoxyl sulfate-induced angiotensinogen expression in proximal tubular cells

2013 ◽  
Vol 304 (7) ◽  
pp. C685-C692 ◽  
Author(s):  
Hidehisa Shimizu ◽  
Shinichi Saito ◽  
Yukihiro Higashiyama ◽  
Fuyuhiko Nishijima ◽  
Toshimitsu Niwa
Keyword(s):  
Nadph Oxidase ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Indoxyl Sulfate ◽  
Pyrrolidine Dithiocarbamate ◽  
Uremic Toxin ◽  
Proximal Tubular Cells ◽  
Induced Expression ◽  
Tubular Cells ◽  
Nadph Oxidase 4 ◽  
Proximal Tubular

In chronic kidney disease (CKD), indoxyl sulfate, a uremic toxin, accumulates in serum, and the expression of angiotensinogen (AGT) is upregulated in renal proximal tubular cells. The present study aimed to determine the relationship between indoxyl sulfate and the upregulation of AGT expression in proximal tubular cells. Indoxyl sulfate induced expression of AGT in rat renal cortex and in cultured human proximal tubular cells (HK-2). In proximal tubular cells, indoxyl sulfate induced phosphorylation of cAMP response element-binding protein (CREB) on Ser-133, and small interfering RNA (siRNA) specific to CREB inhibited indoxyl sulfate-induced AGT expression. Our previous study demonstrated that indoxyl sulfate activated nuclear factor-κB (NF-κB) through reactive oxygen species (ROS) production. NF-κB inhibitors (pyrrolidine dithiocarbamate and isohelenin), NF-κB p65 siRNA, an antioxidant [ N-acetylcysteine (NAC)], and a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor [diphenyleneiodonium (DPI)] suppressed indoxyl sulfate-induced AGT expression. Both NAC and DPI suppressed indoxyl sulfate-induced expression of NF-κB p65 and CREB. CREB siRNA suppressed indoxyl sulfate-induced NF-κB p65 expression, whereas both NF-κB inhibitors and NF-κB p65 siRNA prevented indoxyl sulfate-induced CREB expression. Furthermore, we focused on the expression of NADPH oxidase 4 (NOX4), because indoxyl sulfate induced NOX4 expression in vascular smooth muscle cells and vascular endothelial cells. Indoxyl sulfate induced the expression of NOX4 in proximal tubular cells, which was suppressed by NAC, DPI, NF-κB inhibitors, NF-κB p65 siRNA, and CREB siRNA. Taken together, CREB, NF-κB, and NOX4 coordinately upregulate indoxyl sulfate-induced AGT expression in proximal tubular cells.

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