NQDI 1, An Inhibitor of ASK1 Attenuates Acute Ischemic Renal Injury by Modulating Oxidative Stress and Cell Death

Eter, Eman El

doi:10.2174/18715257113119990085

Cited by 17 publications

(7 citation statements)

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“…Administration of the ASK1 inhibitor NQDI-1 to uninephrectomized rats 1 h prior to commencing 45 min of renal ischemia resulted in protection from kidney oxidative stress, tubular cell apoptosis, loss on renal function, and histological damage (13). This study demonstrated that prophylactic treatment with an ASK1 inhibitor could protect kidneys from ischemia-reperfusion injury and was consistent with previous findings in Ask1 Ϫ/Ϫ mice.…”

Section: Therapeutic Evaluation Of Ask1 Inhibitors In Kidney Diseasesupporting

confidence: 91%

“…Growing interest in ASK1 as a potential therapeutic target has led to the development of selective synthetic inhibitors of ASK1 (Table 1). These ASK1 inhibitors have been shown to have therapeutic benefits in various animal disease models, including multiple sclerosis (19), contact hypersensitivity (43), cardiac and renal ischemia-reperfusion injury (13,17), tumor growth (24), acetaminophen hepatotoxicity (66), and diabetic nephropathy (61) ( Table 1).…”

Section: Therapeutic Evaluation Of Ask1 Inhibitors In Kidney Diseasementioning

confidence: 99%

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ASK1: a new therapeutic target for kidney disease

Tesch

Frank

Nikolic‐Paterson

2016

American Journal of Physiology-Renal Physiology

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Stress-induced activation of p38 MAPK and JNK signaling is a feature of both acute and chronic kidney disease and is associated with disease progression. Inhibitors of p38 MAPK or JNK activation provide protection against inflammation and fibrosis in animal models of kidney disease; however, clinical trials of p38 MAPK and JNK inhibitors in other diseases (rheumatoid arthritis and pulmonary fibrosis) have been disappointing. Apoptosis signal-regulating kinase 1 (ASK1) acts as an upstream regulator for the activation of p38 MAPK and JNK in kidney disease. Mice lacking the Ask1 gene are healthy with normal homeostatic functions and are protected from acute kidney injury induced by ischemia-reperfusion and from renal interstitial fibrosis induced by ureteric obstruction. Recent studies have shown that a selective ASK1 inhibitor substantially reduced renal p38 MAPK activation and halted the progression of nephropathy in diabetic mice, and this has led to a current clinical trial of an ASK1 inhibitor in patients with stage 3 or 4 diabetic kidney disease. This review explores the rationale for targeting ASK1 in kidney disease and the therapeutic potential of ASK1 inhibitors based on current experimental evidence.

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Section: Therapeutic Evaluation Of Ask1 Inhibitors In Kidney Diseasesupporting

confidence: 91%

Section: Therapeutic Evaluation Of Ask1 Inhibitors In Kidney Diseasementioning

confidence: 99%

ASK1: a new therapeutic target for kidney disease

Tesch

Frank

Nikolic‐Paterson

2016

American Journal of Physiology-Renal Physiology

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“…For instance, GS‐459679, a small molecular inhibitor of ASK1, has been developed to rescue IR‐induced myocardium at the risk of death in mice . Furthermore, inhibiting ASK1 by its inhibitor NQD‐1 significantly protects against neuronal cell death after cerebral ischemia and exhibits potent inhibition of oxidative stress and cell death in renal IR injury . Therefore, we believe that blocking the Tollip‐ASK1 axis is translationally promising for hepatic IR injury.…”

Section: Discussionmentioning

confidence: 99%

Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia‐Reperfusion Injury in Mice

et al. 2019

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Hepatic ischemia-reperfusion (IR) injury is the leading cause of liver dysfunction and failure after liver resection or transplantation and lacks effective therapeutic strategies. Here, we applied a systematic proteomic analysis to identify the prominent contributors to IR-induced liver damage and promising therapeutic targets for this condition. Based on an unbiased proteomic analysis, we found that toll-interacting protein (Tollip) expression was closely correlated with the hepatic IR process. RNA sequencing analysis and phenotypic examination showed a dramatically alleviated hepatic IR injury by Tollip deficiency both in vivo and in hepatocytes. Mechanistically, Tollip interacts with apoptosis signal-regulating kinase 1 (ASK1) and facilitates the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6) to ASK1, leading to enhanced ASK1 N-terminal dimerization and the subsequent activation of downstream mitogen-activated protein kinase (MAPK) signaling. Furthermore, the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for Tollip-regulated ASK1-MAPK axis activation. Conclusion: Tollip is a regulator of hepatic IR injury by facilitating ASK1 N-terminal dimerization and the resultant c-Jun N-terminal kinase/p38 signaling activation. Inhibiting Tollip or its interaction with ASK1 might be promising therapeutic strategies for hepatic IR injury.

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“…Following ischemia/reperfusion (I/R) in mice, treatment with ASK1-small interfering RNA significantly attenuates the upregulation of ASK1, which was followed by the reduction of infarction in the ischemic brain ( 18 ). Administration of NQDI-1 attenuated renal dysfunction and histological changes characteristic of renal I/R injury (IRI), accompanied by the upregulation of superoxide dismutase and Bcl-2 in the kidney ( 25 ). Based on the upregulation of ASK1 in the perinatal rat brain following HI, NQDI-1 was intracerebroventricularly injected to determine whether inhibition of ASK1 prevents apoptotic neuronal cell death and brain damage following HI in the perinatal rat.…”

Section: Discussionmentioning

confidence: 99%

“…Arbor, MI, USA), a highly specific ASK1 inhibitor, dissolved in DMSO into the right cerebral hemisphere 30 min prior to HI using a 30-gauge needle with a 5 μ l Hamilton syringe (infusion rate, 1 μ l/min). The NQDN-1 dose (250 nmol/pup) used in the present study was selected, according to a previous report ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death

Huang

Tang

et al. 2016

Molecular Medicine Reports

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Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed protein kinase, which regulates cell fate in numerous injury conditions. Therefore, ASK1 may be a promising novel therapeutic target for injury. However, the expression and distribution of ASK1 in the perinatal brain following hypoxia-ischemia (HI) remains to be elucidated. In the present study, western blotting and immunofluorescence were used to determine the expression and distribution of ASK1 and any associated downstream targets in the perinatal rat brain following HI. NQDI-1, a specific inhibitor of ASK1 was intracerebroventricularly injected following neonatal rats brain insult for neuroprotection. The results revealed an increased expression of ASK1 and this expression was localized to the neurons and astrocytes, compared with the sham controls. Additionally, it was demonstrated that the ASK1/c-Jun N-terminal kinases (JNK) pathway was involved in the brain damage following HI in neonatal rats. Notably, NQDI-1 significantly inhibited the in vivo expression levels of ASK1, phosphorylated (p-)JNK, p-c-Jun, p53 and caspase 3. Reduced acute hypoxic-ischemic cerebral injury and cell apoptosis was observed following the injection of NQDI-1. Collectively, NQDI-1 attenuated acute perinatal hypoxic-ischemic cerebral injury by inhibiting the expression of ASK1 and cell apoptosis. This may be a promising novel neuroprotective inhibitor for perinatal cerebra injury.

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NQDI 1, An Inhibitor of ASK1 Attenuates Acute Ischemic Renal Injury by Modulating Oxidative Stress and Cell Death

Cited by 17 publications

References 0 publications

ASK1: a new therapeutic target for kidney disease

ASK1: a new therapeutic target for kidney disease

Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia‐Reperfusion Injury in Mice

NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death

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