RTA-408 Protects Kidney from Ischemia-Reperfusion Injury in Mice via Activating Nrf2 and Downstream GSH Biosynthesis Gene

Han, Peng; Qin, Zhiqiang; Tang, Jingyuan; Xu, Zhen; Li, Ran; Jiang, Xin; Yang, Chengying; Xing, Qianwei; Qi, Xinxin; Tang, Min; Zhang, Jiexiu; Shen, Baixin; Wang, Wei; Qin, Chao; Zhang, Wei

doi:10.1155/2017/7612182

Cited by 55 publications

(37 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, omaveloxolone demonstrates significant efficacy in rodent models of kidney ischemia-reperfusion injury, multiple sclerosis, diabetic wound healing, and radiationinduced dermatitis. [13][14][15][16] Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, affecting 80-100 million people in the United States. [17] Approximately, 25% of cases of NAFLD progress to nonalcoholic steatohepatitis (NASH), which is defined by steatosis, inflammation, cellular ballooning, and fibrosis.…”

mentioning

confidence: 99%

Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis

Reisman

Ferguson

Lee

et al. 2020

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Omaveloxolone is a potent activator of Nrf2, a master transcriptional regulator of a multitude of cytoprotective functions, including antioxidative, anti‐inflammatory, and mitochondrial bioenergetic effects. Some of the most potent known effects of Nrf2 involve hepatoprotective functions. The purpose of this study was to evaluate the effects of omaveloxolone and TX63682, a closely related structural analog with similar oral bioavailability, in the STAM mouse model of nonalcoholic steatohepatitis (NASH). C57Bl/6 mice received a single subcutaneous injection of streptozotocin two days after birth and were fed a high‐fat diet from 4 to 9 weeks of age. Omaveloxolone and TX63682 were orally administered at doses of 1, 3, and 10 mg/kg/d from 6 to 9 weeks of age. Consistent with the beneficial effects of Nrf2 on hepatoprotection and improved lipid handling, both omaveloxolone and TX63682 decreased hepatic fat deposition, hepatocellular ballooning, inflammatory cell infiltration, and collagen deposition. Omaveloxolone and TX63682 also improved blood glucose control, as evidenced by reductions in nonfasting blood glucose and glycated hemoglobin A1C concentrations. Reductions in liver and serum triglycerides with omaveloxolone and TX63682 treatment were also observed. Both omaveloxolone and TX63682 decreased leptin and increased adiponectin in serum, which is consistent with the anti‐inflammatory and antifibrotic effects observed in the liver. These results were associated with significant induction of Nrf2 target gene expression in the liver, including NAD(P)H:quinone oxidoreductase 1, sulfiredoxin 1, and ferritin heavy chain 1. Overall, these data suggest that omaveloxolone and related Nrf2 activators may be useful for the treatment of NASH.

show abstract

mentioning

confidence: 99%

Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis

Reisman

Ferguson

Lee

et al. 2020

J Biochem & Molecular Tox

View full text Add to dashboard Cite

show abstract

“…Bardoxolone imidazolide was also found to improve survival, renal function, kidney histology and production of pro-inflammatory cytokines in mice subjected to kidney I-R injury (42). Similar beneficial results were observed in mice administered omaveloxolone, another Nrf2 activator (43). Also, the interest in various natural products able to activate Nrf2 is growing.…”

Section: Discussionmentioning

confidence: 65%

Mistimed H<sub>2</sub>S upregulation, Nrf2 activation and antioxidant proteins levels in renal tubular epithelial cells subjected to anoxia and reoxygenation

et al. 2020

View full text Add to dashboard Cite

Ischemia-reperfusion (I-R) injury is involved in the pathogenesis of several human diseases. In the present study, the kinetics of the H 2 S producing enzymes-nuclear factor eryt hroid 2-like 2 (Nrf2)-antioxidant proteins axis under anoxia or reoxygenation was evaluated, as well as its effects on survival of mouse renal proximal tubular epithelial cells (RPTECs). In RPTECs subjected to anoxia and subsequent reoxygenation, reactive oxygen species (ROS) production, lipid peroxidation, ferroptotic cell death, the levels of the H 2 S producing enzymes and H 2 S, the expression of Nrf2 and its transcriptional targets superoxide dismutase-3, glutathione reductase, ferritin H and cystine-glutamate antiporter, as well as apoptosis, and the levels of p53, Bax and phosphorylated p53 were assessed. When needed, the H 2 S producing enzyme inhibitor aminooxyacetate, or the ferroptosis inhibitor α-tocopherol, were used. Reoxygenation induced ferroptosis, whereas anoxia activated the p53-Bax pathway and induced apoptosis. The H 2 S producing enzymes-Nrf2-antioxidant proteins axis was activated only during anoxia and not during reoxygenation, when cellular viability is threatened by ROS overproduction and the ensuing ferroptosis. The activation of the above axis during anoxia ameliorated the effects of the apoptotic p53-Bax pathway, but did not adequately protect against apoptosis. In conclusion, the H 2 S-Nrf2 axis is activated by anoxia, and although it reduces apoptosis, it does not completely prevent apoptotic cell death. Additionally, following reoxygenation, the above axis was not activated. This mistimed activation of the H 2 S producing enzymes-Nrf2-antioxidant proteins axis contributes to reoxygenation-induced cell death. Determining the exact molecular mechanisms involved in reoxygenation-induced cell death may assist in the development of clinically relevant interventions for preventing I-R injury.

show abstract

“…Unfortunately, excessive oxygen induces a burst in production of free radicals, which initiates another wave of biochemical changes and tissue destruction. Therefore, oxidative stress is one dominant factor in I/R injury . IPC is a series involving brief exposure to sublethal ischemia and reperfusion.…”

Section: Discussionmentioning

confidence: 99%

“…The reduction of MDA due to IPC was concurrently accompanied by an additional elevated Nrf2 and HO‐1 protein expression. There is increasing evidence that indicates the renoprotective effect of Nrf2 against renal I/R injury . That is, IPC has a significant impact on the ability of tissues to withstand and survive sustained oxidative insults caused by renal I/R.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence has highlighted the detrimental roles of inflammation, oxidative stress, and apoptosis in pathophysiological initiation and the progression of renal I/R injury. Parallel studies further reveal the beneficial potential that agents with antioxidant, antiinflammatory, or anti-apoptotic effects have, to combat renal I/R injury (3)(4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 96%

See 1 more Smart Citation

Ischemic preconditioning improved renal ischemia/reperfusion injury and hyperglycemia

et al. 2018

IUBMB Life

View full text Add to dashboard Cite

Renal ischemia/reperfusion (I/R) is an alternation of renal hemodynamics, which results in diverse postischemic responses and eventually acute kidney injury. Although renal ischemic preconditioning (IPC) is known to protect the kidney from I/R injury, the precise renoprotective mechanisms are not completely understood. The multiple renoprotective effects of IPC underscore the importance in understanding molecular mechanisms and the targets of action involved. This study aimed to identify the biochemical changes in renal I/R injury and investigate the renoprotective mechanisms of IPC. Herein, renal I/R was produced in adult male Sprague–Dawley rats through the bilateral ligation of renal pedicles for 45 min, followed by reperfusion for 24 h. For the IPC group, rats were subjected to three cycles of 2‐min ischemia, followed by a 5‐min reperfusion, 15 min prior to renal I/R. Our data confirmed the beneficial effects that IPC has on renal I/R injury. IPC‐mediated renoprotection was associated with the resolution of oxidative stress, inflammation, apoptosis, and hyperglycemia. Among the numerous signaling molecules involved in the renoprotective mechanisms of IPC, an elevated protein expression of Nrf2, HO‐1, LC3 II conversion, along with Atg12 and protein phosphorylation of AMPK, as well as a decreased protein phosphorylation of ERK, p38 MAPK, and Akt and NF‐κB DNA binding activity were identified. Importantly, the post renal I/R overproduction of counter‐regulatory hormones, impaired hepatic insulin action, and augmented hepatic gluconeogenesis were improved through IPC. As counter‐regulatory hormones have been implicated in the induction of oxidative stress, inflammation, apoptosis, impaired insulin action, hyperglycemia, and tissue destruction, our findings suggest that counter‐regulatory hormones may well be valuable targets of IPC for combatting renal I/R injury. © 2018 IUBMB Life, 71(3):321–329, 2019

show abstract

RTA-408 Protects Kidney from Ischemia-Reperfusion Injury in Mice via Activating Nrf2 and Downstream GSH Biosynthesis Gene

Cited by 55 publications

References 45 publications

Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis

Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis

Mistimed H<sub>2</sub>S upregulation, Nrf2 activation and antioxidant proteins levels in renal tubular epithelial cells subjected to anoxia and reoxygenation

Ischemic preconditioning improved renal ischemia/reperfusion injury and hyperglycemia

Contact Info

Product

Resources

About