DDAH-2 alleviates contrast medium iopromide-induced acute kidney injury through nitric oxide synthase

2019 ◽  
Vol 133 (23) ◽  
pp. 2361-2378 ◽  
Author(s):  
Heng-Huei Lin ◽  
Tzong-Shyuan Lee ◽  
Shing-Jong Lin ◽  
Yi-Chen Yeh ◽  
Tse-Min Lu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Kidney Injury ◽  
Nitric Oxide Synthase ◽  
Protective Effect ◽  
Contrast Medium ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Ros Generation ◽  
Oxide Synthase

Abstract Background: Contrast medium-induced acute kidney injury (CI-AKI) is one of the most common causes of hospital-acquired acute renal failure. However, the pathogenesis of CI-AKI remains unclear. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor that is largely metabolised by dimethylarginine dimethylaminohydroxylase (DDAH) in humans. Two isoforms of DDAH exist, namely, DDAH-1 and DDAH-2. In the present study, we examined whether the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI. Methods and Results: Exposure to the contrast medium iopromide led to increase in creatinine and blood urea nitrogen (BUN) levels, accumulation of ADMA, increase in reactive oxygen species (ROS) generation, and an inflammatory response in mice kidney tissue. The injection of adenovirus-harbouring DDAH-2 lowered renal ADMA levels and had a reno-protective effect against contrast-medium injury by decreasing cell apoptosis, ROS, and fibrosis. By contrast, contrast medium-induced renal injury was exacerbated in heterozygous DDAH-2 knockout mice. In the in vitro study, overexpression of DDAH-2 increased the levels of nitrite and intracellular cGMP, while the DDAH-2 knockdown induced the opposite effect. These findings were also observed in the in vivo sample. Conclusions: Our findings provide the first evidence that the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI and that the protective effect of DDAH-2 probably arises from the modulation of NOS activity, oxidative stress, and the inflammatory process.

DDAH-2 Alleviates Contrast Medium Iopromide-Induced Acute Kidney Injury Through Nitric Oxide Synthase

2019 ◽  
Author(s):  
Heng-Huei Lin ◽  
Tzong-Shyuan Lee ◽  
Shing-Jong Lin ◽  
Yi-Chen Yeh ◽  
Tse-Min Lu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Kidney Injury ◽  
Nitric Oxide Synthase ◽  
Contrast Medium ◽  
Kidney Injury ◽  
Oxide Synthase

Protective effect of an inhibitor of nitric oxide synthase on sulphur mustard toxicity in vitro

1996 ◽  
Vol 141 (1) ◽  
pp. 138-144 ◽  
Author(s):  
T.W. Sawyer ◽  
P.M. Lundy ◽  
M.T. Weiss
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Protective Effect ◽  
Sulphur Mustard ◽  
Oxide Synthase ◽  
Toxicity In Vitro

scholarly journals Involvement of S100A8/A9-TLR4-NLRP3 Inflammasome Pathway in Contrast-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (1) ◽  
pp. 209-222 ◽  
Author(s):  
Xuexian Tan ◽  
Xiaohe Zheng ◽  
Zena Huang ◽  
Jiaqiong Lin ◽  
Chuli Xie ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Nlrp3 Inflammasome ◽  
Tissue Injury ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Underlying Mechanism ◽  
Male Rats ◽  
Ros Generation

Background: Contrast-induced acute kidney injury (CIAKI) is a common cause of hospital-acquired acute kidney injury (AKI). S100A8/A9-TLR4-NLRP3 inflammasome pathway triggers inflammation, apoptosis and tissue injury in several AKI models. Nevertheless, the underlying mechanism of S100A8/A9-TLR4-NLRP3 inflammasome pathway in CIKAI is not clear. We aimed to investigate the possible role of S100A8/A9-TLR4-NLRP3 inflammasome in the pathophysiology of CIAKI. Methods: We treated male rats and NRK-52E cells by iopromide to establish in vivo and in vitro models of CIAKI. We collected serum and urine samples to detect renal function. We obtained kidney tissue for histological analysis and detection of protein concentration. We used inhibitor of TLR4 and NLRP3-siRNA to further testify their role in CIAKI in NRK-52E cells. Results: Iopromide caused elevation of SCr, BUN and NGAL level, decrease of endogenous creatinine clearance, morphological injury and tubular apoptosis, enhanced IL-1β and IL-18 expression, and increased expression of S100A8/A9, TLR4 and NLRP3 inflammsome. In NRK-52E cells, iopromide caused enhanced apoptotic rates and ROS generation, which could be ameliorated by inhibitor of TLR4 and NLRP3-siRNA. Moreover, inhibition of TLR4 dampened NLRP3 expression. Conclusion: S100A8/A9-TLR4-NLRP3 inflammasome pathway represented a key mechanism of CI-AKI, which provided a potential therapeutic target.

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase

2012 ◽  
Vol 302 (8) ◽  
pp. F1045-F1054 ◽  
Author(s):  
Ana Carolina C. Pessoa de Souza ◽  
Rildo A. Volpini ◽  
Maria Heloísa Shimizu ◽  
Talita Rojas Sanches ◽  
Niels Olsen Saraiva Camara ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Kidney Injury ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Inulin Clearance ◽  
Enos Expression ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-κB activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLP+EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-l-arginine methyl ester (l-NAME) simultaneously with EPO administration (CLP+EPO+l-NAME). A fifth group (CLP+EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP+EPO rats presented significantly higher inulin clearance than did CLP and CLP+EPO+l-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP+EPO rats; and inulin clearance was significantly higher in CLP+EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP+EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-α activation, NF-κB activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-κB downregulation.

scholarly journals Resolvin E1 protects the rat heart against reperfusion injury

2010 ◽  
Vol 299 (1) ◽  
pp. H153-H164 ◽  
Author(s):  
K. T. Keyes ◽  
Y. Ye ◽  
Y. Lin ◽  
C. Zhang ◽  
J. R. Perez-Polo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Eicosapentaenoic Acid ◽  
Protective Effect ◽  
Infarct Size ◽  
Caspase 3 ◽  
Inflammatory Mediator ◽  
Oxide Synthase

The purpose of the present study was to assess whether resolvin E1 (RvE1), an anti-inflammatory mediator derived from eicosapentaenoic acid, would limit myocardial infarct size in the rat. The H9c2 cell line was used to assess whether RvE1 has direct protective effects on cardiomyocytes. In in vivo experiments, Male Sprague-Dawley rats underwent 30 min of ischemia/4 h of reperfusion. Before reperfusion, rats received intravenous RvE1 (0, 0.03, 0.1, or 0.3mg/kg). In in vitro experiments, H9c2 cells were incubated with RvE1 (0, 1, 10, 100, or 1000 nM). Cells were subjected to 18 h of incubation under normoxic conditions, 16 h of hypoxia, or 16 h of hypoxia and 2 h of reoxygenation. In vivo, RvE1 dose dependently reduced infarct size (30.7 ± 1.7% of the area at risk in the control group and 29.1 ± 1.6%, 14.7 ± 1.3%, and 9.0 ± 0.6% in the 0.03, 0.1, and 0.3 mg/kg groups, respectively, P < 0.001). In vitro, RvE1 increased viability and decreased apoptosis in a dose-dependent fashion in cells exposed to hypoxia or hypoxia/reoxygenation. A maximal effect was achieved at a concentration of 100 nM. RvE1 augmented phosphoinositide 3-kinase activity, attenuated caspase-3 activity, and augmented calcium-dependent nitric oxide synthase activity in cells exposed to hypoxia or hypoxia/reoxygenation. RvE1 increased Akt, ERK1/2, and endothelial nitric oxide synthase phosphorylation and attenuated the levels of activated caspase-3 and phosphorylated p38 levels. AG-1478, an EGF receptor tyrosine kinase inhibitor, blocked the protective effect of RvE1 both in vivo and in vitro and attenuated the RvE1-induced increase in Akt and ERK1/2 phosphorylation. In conclusion, RvE1, an anti-inflammatory mediator derived from eicosapentaenoic acid, has a direct protective effect on cardiomyocytes against ischemia-reperfusion injury and limits infarct size when administered intravenously before reperfusion.

scholarly journals Glycyrrhizic Acid Attenuates Sepsis-Induced Acute Kidney Injury by Inhibiting NF-κB Signaling Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Hongyu Zhao ◽  
Min Zhao ◽  
Yu Wang ◽  
Fengchun Li ◽  
Zhigang Zhang
Keyword(s):  
Nitric Oxide ◽  
Acute Kidney Injury ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Glycyrrhizic Acid ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Serum Samples ◽  
Oxide Synthase ◽  
Caecal Ligation And Puncture

Glycyrrhizic acid (GA) is a major active ingredient in licorice. In our study, the effects of GA on acute kidney injury (AKI) in rats and its underlying molecular mechanisms were investigated. The sepsis model was produced by caecal ligation and puncture (CLP) in rats. The molecular and histological experiments were performed in the kidney tissues and serum samples of rats. According to the results obtained, GA alleviated sepsis-induced AKI by improving the pathological changes, decreasing the levels of blood urea nitrogen (BUN), creatinine (Cre), and increasing the survival rate of rats with AKI significantly. The production of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, was markedly inhibited by GA. Moreover, treatment with GA inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and expression levels of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in kidney tissues. Furtherly, the apoptosis in kidney tissue induced by AKI was suppressed by GA. Finally, GA could inhibit the activation of NF-κB signaling pathway. Our study suggests that GA alleviates sepsis-induced AKI by inhibiting the NF-κB signaling pathway, which provides a strong evidence for a new approach for treating sepsis-induced AKI.

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