Beneficial effects of bardoxolone methyl, an Nrf2 activator, on crush-related acute kidney injury in rats

Kadıoğlu, Emine; Tekşen, Yasemin; Koçak, Cengiz; Koçak, Fatma Emel

doi:10.1007/s00068-019-01216-z

Cited by 13 publications

(9 citation statements)

References 41 publications

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“…BM has been proved effective in patients and animal models of certain diseases due to its antioxidant properties including acute kidney injury, acute lung injury, chronic heart failure, and diabetic kidney disease. 12,13,24,25 Therefore, BM may potentially prevent chondrocyte apoptosis through inhibiting oxidative stress. The present study demonstrated that TBHP induced oxidative stress promoted rat chondrocyte apoptosis and ECM degradation.…”

Section: Dovepressmentioning

confidence: 99%

Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in vitro and Alleviates Osteoarthritis in vivo

Pang¹,

Jiang²,

Zhu³

et al. 2021

DDDT

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Oxidative stress-induced chondrocyte apoptosis and extracellular matrix (ECM) degradation plays an important role in the progression of osteoarthritis (OA). Bardoxolone methyl (BM), a semisynthetic triterpenoid, exerts strong effect against oxidative stress. The purpose of the present study was to determine the effectiveness of bardoxolone-methyl (BM) in preventing oxidative stress-induced chondrocyte apoptosis and extracellular ECM degradation in vitro and the role of alleviating OA progression in vivo. Methods: Oxidative damage was induced by 25 mM tert-butyl hydroperoxide (TBHP) for 24 h in rat chondrocytes. 0.025 and 0.05 µM bardoxolone-methyl (BM) were used in vitro treatment. Ex-vivo cartilage explant model was established to evaluate the effect of BM on oxidative stress-induced ECM degradation. The mouse OA model was induced by surgical destabilization of the medial meniscus. Results: In vitro, 0.025 and 0.05 µM BM reduced TBHP-induced excessive ROS generation, improved cell viability, increased malondialdehyde level and decreased superoxide dismutase level. 0.025 and 0.05 µM BM prevented TBHP-induced mitochondrial damage and apoptosis in chondrocytes BM activated heme oxygenase-1 (HO-1)/NADPH quinone oxidoreductase 1 (NOQ1) signaling pathway through targeting nuclear factor erythroid derived-2-related factor 2 (Nrf2). Additionally, BM treatment enhanced the expression levels of aggrecan and collagen II and inhibited the expression levels of matrix metalloproteinase 9 (MMP 9), MMP 13, Bax and cleaved-caspase-3. BM increased proteoglycan staining area and IOD value in ex vivo cultured experiment cartilage explants and improved the OARSI score, stands, max contact mean intensity, print area and duty cycle in mouse OA model. Conclusion: BM prevented oxidative stress-induced chondrocyte apoptosis and ECM degradation in vitro and alleviated OA in vivo, suggesting that BM serves as an effective drug for treatment with OA.

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Section: Dovepressmentioning

confidence: 99%

Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in vitro and Alleviates Osteoarthritis in vivo

Pang¹,

Jiang²,

Zhu³

et al. 2021

DDDT

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“…Clinical studies have shown that BM can achieve anti-inflammatory and anti-oxidant effects by activating nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibiting nuclear factor-jB (NF-jB) [74] by effectively improving glomerular filtration rate in patients with chronic kidney disease (CKD) [75]. Kadioglu et al [76] showed that BM treatment can improve AKI in the CS rat model. These results also suggested that BM may reduce crush kidney injury by reducing the expression of TNF-a and TGF-b.…”

Section: Bardoxolone Methyl (Bm)mentioning

confidence: 99%

“…Kadioglu et al. [ 76 ] showed that BM treatment can improve AKI in the CS rat model. These results also suggested that BM may reduce crush kidney injury by reducing the expression of TNF-α and TGF-β.…”

Section: Chemical Drugsmentioning

confidence: 99%

Emerging medical therapies in crush syndrome – progress report from basic sciences and potential future avenues

Wang

et al. 2020

Renal Failure

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Crush injury is a disease that is commonly found in victims of earthquakes, debris flows, mine disasters, explosions, terrorist attacks, local wars, and other accidents. The complications that arise due to the crush injury inflicted on victims give rise to crush syndrome (CS). If not treated in time, the mortality rate of CS is very high. The most important measure that can be taken to reduce mortality in such situations is to immediately start treatment. However, the traditional treatment methods such as fluid resuscitation, diuresis, and hemodialysis are not feasible enough to be carried out at the disaster scene. So there is a need for developing new treatments that are efficient and convenient. Because it is difficult to diagnose in the disaster area and reach the treatment equipment and treat on time. It has become a new research needs to be directed into identifying new medical treatment targets and methods using the etiology and pathophysiological mechanisms of CS. In recent years, a large number of new anti-oxidant and anti-inflammatory drug therapies have been shown to be highly efficacious in CS rat/mouse models. Some of them are expected to become specific drugs for the emergency treatment of a large number of patients who may develop CS in the aftermath of earthquakes, wars, and other disasters in the future. Hence, we have reviewed the latest research on the medical therapy of CS as a source for anyone wishing to pursue research in this direction.

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“…Crush syndrome (CS), also known as traumatic rhabdomyolysis syndrome, is an acute clinical syndrome characterized by acute kidney injury (AKI), hyperkalemia, myoglobinuria, hypovolemic shock, etc., and is caused by the release of muscle breakdown products into the blood circulation after prolonged compression of skeletal muscles [ 1 , 2 ]. It often occurs in natural disasters such as earthquakes, tsunamis, and mudslides and human-made disasters such as wars and terrorism [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, AKI is a main life-threatening complication of CS, and CS-AKI has high morbidity and mortality. At present, myoglobin is well accepted as the main pathogenic factor, as it exerts direct toxic effects and causes tubular obstruction in the kidney [ 2 , 6 ]. Fluid resuscitation and hemodialysis are the most effective strategies to prevent and treat CS-AKI [ 7 , 8 ], but they are merely symptomatic treatments.…”

Section: Introductionmentioning

confidence: 99%

RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model

Wang

et al. 2021

Military Med Res

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Background Acute kidney injury (AKI) is the main life-threatening complication of crush syndrome (CS), and myoglobin is accepted as the main pathogenic factor. The pattern recognition receptor retinoicacid-inducible gene I (RIG-I) has been reported to exert anti-viral effects function in the innate immune response. However, it is not clear whether RIG-I plays a role in CS-AKI. The present research was carried out to explore the role of RIG-I in CS-AKI. Methods Sprague-Dawley rats were randomly divided into two groups: the sham and CS groups (n = 12). After administration of anesthesia, the double hind limbs of rats in the CS group were put under a pressure of 3 kg for 16 h to mimic crush conditions. The rats in both groups were denied access to food and water. Rats were sacrificed at 12 h or 36 h after pressure was relieved. The successful establishment of the CS-AKI model was confirmed by serum biochemical analysis and renal histological examination. In addition, RNA sequencing was performed on rat kidney tissue to identify molecular pathways involved in CS-AKI. Furthermore, NRK-52E cells were treated with 200 μmol/L ferrous myoglobin to mimic CS-AKI at the cellular level. The cells and cell supernatant samples were collected at 6 h or 24 h. Small interfering RNAs (siRNA) was used to knock down RIG-I expression. The relative expression levels of molecules involved in the RIG-I pathway in rat kidney or cells samples were measured by quantitative Real-time PCR (qPCR), Western blotting analysis, and immunohistochemistry (IHC) staining. Tumor necrosis factor-α (TNF-α) was detected by ELISA. Co-Immunoprecipitation (Co-IP) assays were used to detect the interaction between RIG-I and myoglobin. Results RNA sequencing of CS-AKI rat kidney tissue revealed that the different expression of RIG-I signaling pathway. qPCR, Western blotting, and IHC assays showed that RIG-I, nuclear factor kappa-B (NF-κB) P65, p-P65, and the apoptotic marker caspase-3 and cleaved caspase-3 were up-regulated in the CS group (P < 0.05). However, the levels of interferon regulatory factor 3 (IRF3), p-IRF3 and the antiviral factor interferon-beta (IFN-β) showed no significant changes between the sham and CS groups. Co-IP assays showed the interaction between RIG-I and myoglobin in the kidneys of the CS group. Depletion of RIG-I could alleviate the myoglobin induced expression of apoptosis-associated molecules via the NF-κB/caspase-3 axis. Conclusion RIG-I is a novel damage-associated molecular patterns (DAMPs) sensor for myoglobin and participates in the NF-κB/caspase-3 signaling pathway in CS-AKI. In the development of CS-AKI, specific intervention in the RIG-I pathway might be a potential therapeutic strategy for CS-AKI.

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Beneficial effects of bardoxolone methyl, an Nrf2 activator, on crush-related acute kidney injury in rats

Cited by 13 publications

References 41 publications

Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in vitro and Alleviates Osteoarthritis in vivo

Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in vitro and Alleviates Osteoarthritis in vivo

Emerging medical therapies in crush syndrome – progress report from basic sciences and potential future avenues

RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model

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