Heme oxygenase-1 ameliorates kidney ischemia-reperfusion injury in mice through extracellular signal-regulated kinase 1/2-enhanced tubular epithelium proliferation

Chen, Hsin Hung; Lu, Pei Jung; Chen, Bo Ron; Hsiao, Michael; Ho, Wen Yu; Tseng, Ching Jiunn

doi:10.1016/j.bbadis.2015.07.018

Cited by 30 publications

(23 citation statements)

References 39 publications

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“…It has been shown that HO-1 induction ameliorates acute and chronic kidney injury such as ischemia-reperfusion (Chen et al 2015), cisplatin (Al-Kahtani et al 2014), and 5/6 nephrectomy (Desbuards et al 2009). On the other hand, the inhibition of this enzyme was found to aggravate renal damage (Ishikawa et al 2001;Takizawa et al 1998).…”

Section: R a F Tmentioning

confidence: 99%

Vascular function and arginine and dimethylarginines in gentamicin-induced renal failure: a possible effect of heme oxygenase 1 inducer hemin

Aycan-Ustyol

Kabasakal

Bekpınar

et al. 2017

Can. J. Physiol. Pharmacol.

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Increased oxidative stress and disturbance in nitric oxide bioavailability lead to endothelial dysfunction and cardiovascular complication in renal disease. Gentamicin (GM), a commonly used antibiotic exhibits a toxic effect on renal proximal tubules. Prevention of its nephrotoxicity is important. Therefore, we investigated whether heme oxygenase (HO)-1 induction influenced kidney and vascular function in GM-administered rats. GM (100 mg/kg/day; ip) was given to rats alone or together with hemin (20 mg/kg/alternate days; ip.) for 14 days. Plasma and kidney L-arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) as well as kidney 4-hydroxynonenal (HNE) levels and myeloperoxidase (MPO) activity were measured. Histopathologic examinations of kidney and relaxation and contraction responses of aorta were also examined.GM increased serum SDMA, urea nitrogen (BUN), and creatinine levels and caused histopathologic alterations in kidney. GM elevated HO-1 protein and mRNA expressions, 4-HNE level, MPO activity and decreased antioxidant enzyme activities and L-arginine levels in kidney. Decreased relaxation and contraction were detected in the aorta. Hemin restored renal oxidative stress and inflammatory changes together with vascular dysfunction, but did not affect SDMA, BUN, and creatinine levels. It is concluded that HO-1 induction may be effective in improving renal oxidative stress, inflammation and vascular dysfunction mediated by GM.

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Section: R a F Tmentioning

confidence: 99%

Vascular function and arginine and dimethylarginines in gentamicin-induced renal failure: a possible effect of heme oxygenase 1 inducer hemin

Aycan-Ustyol

Kabasakal

Bekpınar

et al. 2017

Can. J. Physiol. Pharmacol.

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“…When IRI occurs, Keap1 undergoes conformational change and activates Nrf2, resulting in cellular protection against oxidative stress and enhancement of cell growth and survival [12, 13]. Hemeoxygenase-1 (HO-1) is one of the antioxidant response element (ARE)–dependent phase II detoxifying enzymes and antioxidants that are regulated by the redox-sensitive transcription factor Nrf2 [14-16]. Activation of Nrf2 induces HO-1 expression, suggesting that Nrf2 is essential for HO-1–mediated cytoprotection against IRI [17, 18].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Alleviates Inflammatory Responses and Oxidative Stress in Rat Kidney Ischemia-Reperfusion Injury and H2O2-Induced NRK-52E Cells via the Nrf2/TLR4/NF-κB Pathway

Wang

et al. 2018

Cell Physiol Biochem

100

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Background: Ischemia-reperfusion injury (IRI) is one of the major causes of postoperative renal allograft dysfunction, which is mainly the result of proinflammatory reactions including inflammatory responses, oxidative stress, and metabolic disorders. Resveratrol (RSV) plays an important role in protecting various organs in IRI because it reduces oxidative stress, lessens the inflammatory response, and exerts anti-apoptotic effects. The aim of this study was to demonstrate the renoprotective effect of RSV in inhibiting inflammatory responses, reducing oxidative stress, and decreasing cell apoptosis in vivo and in vitro. Methods: RSV was administered before renal ischemia and H₂O₂ induction. Serum and kidneys were harvested 24 h after reperfusion and NRK-52E cells were collected 4 h after H₂O₂ stimulation. Serum creatinine and blood urea nitrogen were used to assess renal function. Hematoxylin and eosin staining was performed to assess histological injury. Quantitative real-time PCR and enzyme-linked immunosorbent assay were used to assess proinflammatory cytokine expression. Oxidative stress–related proteins, such as Nrf2 and TLR4, were evaluated by western blot. Terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling assay was used to detect apoptotic cells in tissues, and western blot was used to evaluate the expression of caspase-3, -8, and -9 in this study. Results: RSV inhibited inflammatory responses and improved renal function after renal IRI. Additionally, RSV decreased oxidative stress and reduced cell apoptosis by upregulating Nrf2 expression, downregulating the TLR4/NF-κB signaling pathway, and by decreasing caspase-3 activity and caspase cascades. Conclusion: Our study demonstrated the mechanisms underlying RSV renoprotection. We found that RSV exerts its greatest effects by blocking inflammatory responses, lowering oxidative stress, and reducing apoptosis via the Nrf2/TLR4/NF-κB pathway.

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“…Total and phosphorylated ERK1/2 and p38 proteins were measured in NRK-52E cells exposed to 24 to 72 h of hypoxia. As shown in Figure 2 (A and B), hypoxia induced a large increase in phosphorylated ERK1/2 (P-ERK1/2) in the NRK-52E cells at all 3 time points (24,48, and 72 h) of hypoxic exposure (P < 0.001, n ¼ 4) without any significant change in total ERK 1/2 (T-ERK1/2) or ERK1/2 messenger RNA (Fig. 3).…”

Section: Effect Of Hypoxia On Erk1/2 and P38 Phosphorylationmentioning

confidence: 73%

“…44,45 Among them, the role of ERK1/2 has been considered a protective factor for cell survival, while p38 is considered a factor for cell injury. 20,[46][47][48][49] In cultured rat cortical neurons, hypoxia differentially regulated the phosphorylation of p38 and ERK1/2, 27 whereas in the rat hippocampal slices, the phosphorylation of both p38 and ERK2, but not ERK1, was upregulated in response to hypoxia. 50 It is also reported that chronic inflammatory and apoptotic cascades that are stimulated by p38 and JNK, but not ERK pathways, contribute to the pathogenesis of the chronic intermittent hypoxia-induced renal injury.…”

Section: Discussionmentioning

confidence: 97%

ERK and p38 upregulation versus Bcl-6 downregulation in rat kidney epithelial cells exposed to prolonged hypoxia

Luo

Shi

et al. 2017

cell transplant

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Hypoxia is a common cause of kidney injury and a major issue in kidney transplantation. Mitogen-activated protein kinases (MAPKs) are involved in the cellular response to hypoxia, but the precise roles of MAPKs in renal cell reactions to hypoxic stress are not well known yet. This work was conducted to investigate the regulation of extracellular signal-regulated kinase-1 and -2 (ERK1/2) and p38 and their signaling-relevant molecules in kidney epithelial cells exposed to prolonged hypoxia. Rat kidney epithelial cells Normal Rat Kidney (NRK)-52E were exposed to hypoxic conditions (1% O 2 ) for 24 to 72 h. Cell morphology was examined by light microscopy, and cell viability was checked by 3-The expression of ERK1/2 and p38 MAPK, as well as their signaling-related molecules, was measured by Western blot and real-time polymerase chain (RT-PCR) reaction. At the 1% oxygen level, cell morphology had no appreciable changes compared to the control up to 72 h of exposure under light microscopy, whereas the results of MTS showed a slight but significant reduction in cell viability after 72 h of hypoxia. On the other hand, ERK1/2 and p38 phosphorylation remarkably increased in these cells after 24 to 72 h of hypoxia. In sharp contrast, the expression of transcription factor B-cell lymphoma 6 (Bcl-6) was significantly downregulated in response to hypoxic stress. Other intracellular molecules relevant to the ERK1/2 and p38 signaling pathway, such as protein kinase A, protein kinase C, Bcl-2, nuclear factor erythroid 2-related factor 2, tristetraprolin, and interleukin-10(IL-10), had no significant alterations after 24 to 72 h of hypoxic exposure. We conclude that hypoxic stress increases the phosphorylation of both ERK1/2 and p38 but decreases the level of Bcl-6 in rat kidney epithelial cells.

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Heme oxygenase-1 ameliorates kidney ischemia-reperfusion injury in mice through extracellular signal-regulated kinase 1/2-enhanced tubular epithelium proliferation

Cited by 30 publications

References 39 publications

Vascular function and arginine and dimethylarginines in gentamicin-induced renal failure: a possible effect of heme oxygenase 1 inducer hemin

Vascular function and arginine and dimethylarginines in gentamicin-induced renal failure: a possible effect of heme oxygenase 1 inducer hemin

Resveratrol Alleviates Inflammatory Responses and Oxidative Stress in Rat Kidney Ischemia-Reperfusion Injury and H2O2-Induced NRK-52E Cells via the Nrf2/TLR4/NF-κB Pathway

ERK and p38 upregulation versus Bcl-6 downregulation in rat kidney epithelial cells exposed to prolonged hypoxia

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