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 A Novel Antioxidant Protects Against Contrast Medium-Induced Acute Kidney Injury in Rats

2020 ◽  
Vol 11 ◽  
Author(s):  
Shuo Huang ◽  
Yanyan Tang ◽  
Tianjun Liu ◽  
Ning Zhang ◽  
Xueyan Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Superoxide Dismutase ◽  
Renal Function ◽  
Cytochrome C ◽  
Caspase 3 ◽  
Mitochondrial Protein ◽  
Kidney Injury ◽  
High Efficient ◽  
Superoxide Dismutase 2

Many studies proposed that oxidative stress and apoptosis are key mechanisms in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). Xylose-pyrogallol conjugate (XP) is an original effective antioxidant that showed decent antioxidant and anti-apoptosis effect before. Thus the therapeutic effect and mechanism of XP in preventing CI-AKI in the short and long term were investigated in this research. Renal function and histological grade were evaluated to determine the severity of renal injury. Kidney samples were then collected for the measurement of oxidative stress markers and the detection of apoptosis. Transmission electron microscopy (TEM) and western blot of mitochondrial protein were utilized for the analysis of the mitochondrial conditions. The results demonstrated that the CI-AKI rats caused a significant decrease in renal function accompanied by a remarkable increase in Malondialdehyde (MDA), bax, caspase-3, cytochrome c (Cyt C) level, TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and damaged mitochondria, while a decline in antioxidase activities and mitochondrial superoxide dismutase 2 (SOD2) expression compared with the control rats. However, when XP (50 or 100 or 200 mg/kg/day) was given orally for consecutive 7 days before CI-AKI modeling, XP (200 mg/kg) showed a better capability to restore renal dysfunction, histopathological appearance, the level of apoptosis, mitochondrial damage, oxidative stress, and fibrosis generation without interference in computed tomographic imaging. Our study indicated that antioxidant XP played a nephroprotective role probably via antiapoptotic and antioxidant mechanisms. Besides, XP may regulate the mitochondria pathway via decreasing the ratio of bax/bcl-2, inhibiting caspase-3 expression, cytochrome c release, and superoxide dismutase 2 activity. Overall, XP as a high-efficient antioxidant may have the potentials to prevent CI-AKI.

p53-Mediated Oxidative Stress and Tubular Injury in Rats with Glycerol-Induced Acute Kidney Injury

2011 ◽  
Vol 33 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Eduardo Homsi ◽  
Sergio Mota da Silva, Jr. ◽  
Silvano Machado de Brito ◽  
Elisa Bouçada Inácio Peixoto ◽  
Jose Butori Lopes de Faria ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Tubular Injury

scholarly journals Inhibition of Mitochondrial Complex I Aggravates Folic Acid-Induced Acute Kidney Injury

2019 ◽  
Vol 44 (5) ◽  
pp. 1002-1013 ◽  
Author(s):  
Wen Zhang ◽  
Yunwen Yang ◽  
Huiping Gao ◽  
Yue Zhang ◽  
Zhanjun Jia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Folic Acid ◽  
Mitochondrial Dysfunction ◽  
Complex I ◽  
Kidney Injury ◽  
Mitochondrial Complex I ◽  
Tubular Injury ◽  
Mitochondrial Complex ◽  
Renal Tubular

Background: Some researches revealed that mitochondrial dysfunction is associated with various kidney injury. However, the role of mitochondrial dysfunction in the pathogenesis of acute kidney injury (AKI) still needs evidence. Methods: We evaluated the effect of mitochondrial complex I inhibitor rotenone on folic acid (FA)-induced AKI in mice. Results: Strikingly, the mice pretreated with rotenone at a dose of 200 ppm in food showed exacerbated kidney injury as shown by higher levels of blood urea nitrogen and creatinine compared with FA alone group. Meanwhile, both renal tubular injury score and the expression of renal tubular injury marker neutrophil gelatinase-associated lipocalin were further elevated in rotenone-pretreated mice, suggesting the deteriorated renal tubular injury. Moreover, the decrements of mitochondrial DNA copy number and the expressions of mitochondrial Cytochrome c oxidase subunit 1, mitochondrial NADH dehydrogenase subunit 1, and mitochondria-specific superoxide dismutase (SOD2) in the kidneys of FA-treated mice were further reduced in rotenone-pretreated mice, indicating the aggravated mitochondrial damage. In parallel with the SOD2 reduction, the oxidative stress markers of malondialdehyde and HO-1 displayed greater increment in AKI mice with rotenone pretreatment in line with the deteriorated apoptotic response and inflammation. Conclusion: Our results suggested that the inhibition of mitochondrial complex I activity aggravated renal tubular injury, mitochondrial damage, oxidative stress, cell apoptosis, and inflammation in FA-induced AKI.

scholarly journals TGF-β-mediated NADPH oxidase 4-dependent oxidative stress promotes colistin-induced acute kidney injury

2018 ◽  
Vol 73 (4) ◽  
pp. 962-972 ◽  
Author(s):  
Bo Young Jeong ◽  
Se-Ra Park ◽  
Sungkwon Cho ◽  
Seong-Lan Yu ◽  
Hoi Young Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Nadph Oxidase ◽  
Kidney Injury ◽  
Nadph Oxidase 4

scholarly journals Tamm-Horsfall protein-deficient thick ascending limbs promote injury to neighboring S3 segments in an MIP-2-dependent mechanism

2011 ◽  
Vol 300 (4) ◽  
pp. F999-F1007 ◽  
Author(s):  
Tarek M. El-Achkar ◽  
Ruth McCracken ◽  
Michael Rauchman ◽  
Monique R. Heitmeier ◽  
Ziyad Al-Aly ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Wild Type Mouse ◽  
Neutrophil Infiltration ◽  
Apical Surface ◽  
Dependent Manner ◽  
Tubular Injury ◽  
Wild Type ◽  
Direct Role

Tamm-Horsfall protein (THP) is a glycoprotein expressed exclusively in thick ascending limbs (TAL) of the kidney. We recently described a novel protective role of THP against acute kidney injury (AKI) via downregulation of inflammation in the outer medulla. Our current study investigates the mechanistic relationships among the status of THP, inflammation, and tubular injury. Using an ischemia-reperfusion model in wild-type and THP−/− mice, we demonstrate that it is the S3 proximal segments but not the THP-deficient TAL that are the main targets of tubular injury during AKI. The injured S3 segments that are surrounded by neutrophils in THP−/− mice have marked overexpression of neutrophil chemoattractant MIP-2 compared with wild-type counterparts. Neutralizing macrophage inflammatory protein-2 (MIP-2) antibody rescues S3 segments from injury, decreases neutrophil infiltration, and improves kidney function in THP−/− mice. Furthermore, using immunofluorescence volumetric imaging of wild-type mouse kidneys, we show that ischemia alters the intracellular translocation of THP in the TAL cells by partially shifting it from its default apical surface domain to the basolateral domain, the latter being contiguous to the basolateral surface of S3 segments. Concomitant with this is the upregulation, in the basolateral surface of S3 segments, of the scavenger receptor SRB-1, a putative receptor for THP. We conclude that TAL affects the susceptibility of S3 segments to injury at least in part by regulating MIP-2 expression in a THP-dependent manner. Our findings raise the interesting possibility of a direct role of basolaterally released THP on regulating inflammation in S3 segments.

Abstract P544: Osteopontin Deficiency Decreases Autophagy and Exacerbates Tubular Injury in Acute Kidney Injury Induced by Folic Acid

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Tomoaki Nagao ◽  
Takafumi Okura ◽  
Akiko Tanino ◽  
Ken-ichi Miyoshi ◽  
Masayoshi Kukida ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Folic Acid ◽  
Kidney Injury ◽  
Immunohistochemical Analysis ◽  
Tubular Injury ◽  
Histological Changes ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Osteopontin (OPN), a secreted glycosylated phosphoprotein and pro-inflammatory cytokine, has been implicated in the pathology of several renal conditions, especially renal fibrosis in chronic kidney disease. OPN is slightly expressed in renal tubular cells in normal condition, but after acute tubular injury, OPN is highly induced in these cells. However, the role of induced OPN is still unclear. The aim of this study was to clarify the roles of OPN in acute kidney injury (AKI). AKI was induced in wild type (WT) and OPN knockout (KO) mice by using folic acid (FA) injection (0.35mg/kg). After 2days of injection, 34% of WT mice died, whereas 54% of KO died from renal failure. Kidneys from survived mice were removed and the renal histological changes, protein expression were examined. BUN and Creatinine levels were markedly elevated in WT-AKI and KO-AKI mice (BUN: WT-sham; 25.7±4.7mg/dl, WT-AKI; 315.0±173.2mg/dl, KO-AKI; 337.7±163.7mg/dl, Creatinine: WT-sham; 0.08±0.03 mg/dl, WT-AKI; 1.60±0.87 mg/dl, KO-AKI; 1.80±0.94 mg/dl). Renal OPN mRNA expression was increased in WT-AKI mice compared to WT-sham mice (p<0.05). High levels of OPN expression in renal tubular cells were induced in WT-AKI mice. TUNEL positive tubular cells were increased in KO-AKI mice compared to WT-AKI mice. In immunohistochemical analysis, Kidney injury molecules 1 (Kim-1) positive tubular cells were also highly increased in KO-AKI mice compared to WT-AKI mice. In contrast, LC3B (autophagy related protein) positive tubular cells were decreased in KO-AKI mice compared to WT-AKI mice. These results indicate that OPN deficiency exacerbates tubular injury via through the inhibiting autophagy in folic acid induced AKI mice.

scholarly journals 5-HT1F receptor regulates mitochondrial homeostasis and its loss potentiates acute kidney injury and impairs renal recovery

2018 ◽  
Vol 315 (4) ◽  
pp. F1119-F1128 ◽  
Author(s):  
Whitney S. Gibbs ◽  
Justin B. Collier ◽  
Morgan Morris ◽  
Craig C. Beeson ◽  
Judit Megyesi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Kidney Injury ◽  
Renal Recovery ◽  
Tubular Injury ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Dna Copy Number ◽  
Proximal Tubular

Our laboratory previously reported that agonists of the 5-hydoxytryptamine 1F (5-HT1F) receptor induce renal mitochondrial biogenesis (MB) and that stimulation of the 5-HT1F receptor following ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) accelerated the recovery of renal function in mice. The goal of this study was to examine the contribution of the 5-HT1F receptor in the regulation of renal mitochondrial homeostasis and renal function in naïve and injured mice. Although 5-HT1F receptor knockout (KO) mice were healthy and fertile, and did not exhibit renal dysfunction, renal mitochondrial DNA copy number and mitochondrial fission gene expression increased at 10 wk of age. The 5-HT1F receptor KO mice exhibited greater proximal tubular injury and diminished renal recovery after I/R-induced AKI compared with wild-type mice. These findings were associated with persistent suppression of renal cortical MB and ATP levels after injury. In summary, the 5-HT1F receptor is a component of physiological MB regulation in the kidney, and its absence potentiates renal injury and impedes recovery.

scholarly journals Immunoglobulin-A Vasculitis With Renal Involvement in a Patient With COVID-19: A Case Report and Review of Acute Kidney Injury Related to SARS-CoV-2

2021 ◽  
Vol 8 ◽  
pp. 205435812199168
Author(s):  
Nicholas L. Li ◽  
Adam B. Papini ◽  
Tiffany Shao ◽  
Louis Girard
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Abdominal Pain ◽  
Renal Biopsy ◽  
Kidney Injury ◽  
Iga Vasculitis ◽  
Tubular Injury ◽  
Raas Blockade ◽  
Purpuric Rash ◽  
New Onset

Rationale: Acute kidney injury is a common complication of COVID-19 and is associated with significantly increased mortality. The most frequent renal biopsy finding with SARS-CoV-2 infection is acute tubular injury; however, new onset glomerular diseases have been reported. The development of persistent urinary abnormalities in patients with COVID-19 should prompt consideration for renal biopsy to rule out glomerulonephritis. Presenting Concerns: A 30-year-old man with no prior medical history presented to the emergency department with symptoms of COVID-19 and new onset painful purpuric rash, arthralgia, and abdominal pain. SARS-CoV-2 infection was confirmed with nucleic acid testing and laboratory investigations revealed preserved renal function with dysmorphic hematuria and nephrotic range proteinuria. Diagnosis: A skin biopsy of the purpuric rash was performed, which demonstrated leukocytoclastic vasculitis. Renal biopsy revealed focally crescentic and segmentally necrotizing IgA nephropathy. Overall, given the clinical syndrome of glomerulonephritis with purpuric rash, arthralgia, and abdominal pain, the presentation is most in keeping with a diagnosis of IgA vasculitis in the setting of COVID-19. Interventions: The patient was treated conservatively for COVID-19 in the community. A 7-day course of prednisone was started for the vasculitic rash. IgA nephropathy was managed conservatively with blood pressure control and RAAS blockade with losartan. Outcomes: With conservative management, the patient’s COVID-19 symptoms resolved completely and he did not require hospital admission. Following prednisone therapy, the patient’s rash, arthralgia, and abdominal pain improved. However, despite resolution of COVID-19, hematuria and proteinuria persisted. With the initiation of RAAS blockade, renal function remained stable and proteinuria improved dramatically at 6 weeks. Novel Findings: De novo glomerulonephritis is a renal manifestation of SARS-CoV-2 infection beyond acute tubular injury. IgA vasculitis appears to be a rare complication of COVID-19.

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