Heme oxygenase-1 induction contributes to renoprotection by G-CSF during rhabdomyolysis-associated acute kidney injury

Granulocyte colony-stimulating factor (G-CSF) is renoprotective during acute kidney injury (AKI) induced by ischemia and cisplatin nephrotoxicity; however, the underlying mechanism is not entirely clear. Rhabdomyolysis is another important clinical cause of AKI, due to the release of nephrotoxins (e.g., heme) from disrupted muscles. The current study has determined the effects of G-CSF on rhabdomyolysis-associated AKI using in vivo and in vitro models. In C57BL/6 mice, intramuscular injection of glycerol induced AKI, which was partially prevented by G-CSF pretreatment. Consistently, glycerol-induced renal tissue damage was ameliorated by G-CSF. In addition, animal survival following the glycerol injection was improved from ∼30 to ∼70% by G-CSF. In cultured renal tubular cells, hemin-induced apoptosis was also suppressed by G-CSF. Interestingly, G-CSF induced heme oxygenase-1 (HO-1, a critical enzyme for heme/hemin degradation and detoxification) in both cultured tubular cells and mouse kidneys. Blockade of HO-1 with protoporphyrin IX zinc(II) (ZnPP) could largely diminish the protective effects of G-CSF. Together, these results demonstrated the renoprotective effects of G-CSF in rhabdomyolysis-associated AKI. Notably, G-CSF may directly protect against tubular cell injury under the disease condition by inducing HO-1.

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α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5

AJP Renal Physiology ◽

10.1152/ajprenal.00143.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. F1443-F1453 ◽

Cited By ~ 46

Author(s):

Chung-Hsi Hsing ◽

Chiou-Feng Lin ◽

Edmund So ◽

Ding-Ping Sun ◽

Tai-Chi Chen ◽

...

Keyword(s):

Acute Kidney Injury ◽

Histone Deacetylases ◽

Trichostatin A ◽

Histone H3 ◽

Cecal Ligation ◽

Kidney Injury ◽

Protective Effects ◽

Tnf Α

Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro , the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF-α, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 μg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-α, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-α, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-α, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an α2-AR antagonist. With DEX treatment, the LPS-induced TNF-α expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-α, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF-α and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.

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miR-125b Disrupts Mitochondrial Dynamics via Targeting Mitofusin 1 in Cisplatin-Induced Acute Kidney Injury

Kidney Diseases ◽

10.1159/000520140 ◽

2021 ◽

pp. 1-11

Author(s):

Yue Zhao ◽

Yue Lang ◽

Mingchao Zhang ◽

Shaoshan Liang ◽

Xiaodong Zhu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Kidney Injury ◽

Immunofluorescent Staining ◽

Luciferase Reporter ◽

Mitochondrial Fragmentation ◽

Tubular Cells ◽

Renal Tubular Cells

Background: Mitochondria are dynamic organelles whose structure are maintained by continuous fusion and fission. During acute kidney injury (AKI) progression, mitochondrial fission in renal tubular cells was elevated, characterized by mitochondrial fragmentation. It is tightly associated with mitochondrial dysfunction, which has been proven as a critical mechanism responsible for AKI. However, the initiating factor for the disruption of mitochondrial dynamics in AKI was not well understood. Objectives: To explore the molecular mechanisms of mitochondrial disorders and kidney damage. Methods: We established cisplatin-induced AKI model in C57BL/6 mice and proximal tubular cells, and detected the expression of miR-125b by qPCR. Then we delivered miR-125b antagomir after cisplatin treatment in mice via hydrodynamic-based gene transfer technique. Subsequently, we performed luciferase reporter and immunoblotting assays to prove miR-125b could directly modulate mitofusin1 (MFN1) expression. We also tested the role of miR-125b in mitochondrial and renal injury through immunofluorescent staining, qPCR, and immunoblotting assays. Results: miR-125b levels were induced in cisplatin-challenged mice and cultured tubular cells. Anti-miR-125b could effectively alleviate cisplatin-induced mitochondrial fragmentation and kidney injury both in vitro and in vivo. Furthermore, miR-125b could directly regulate MFN1, which is a key regulator of mitochondrial fusion. Our study indicated that miR-125b is upregulated during cisplatin-induced AKI. Inhibition of miR-125b may suppress mitochondrial and renal damage through upregulating MFN1. This study suggests that miR-125b could be a potential therapeutic target in AKI.

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Heme Oxygenase-1, a Key Enzyme for the Cytoprotective Actions of Halophenols by Upregulating Nrf2 Expression via Activating Erk1/2 and PI3K/Akt in EA.hy926 Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/7028478 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 6

Author(s):

Xiu E. Feng ◽

Tai Gang Liang ◽

Jie Gao ◽

De Peng Kong ◽

Rui Ge ◽

...

Keyword(s):

Heme Oxygenase ◽

Antioxidant Activities ◽

Heme Oxygenase 1 ◽

Protective Effects ◽

Key Enzyme ◽

Ea.Hy926 Cells ◽

Anti Inflammatory ◽

Mechanistic Basis

Increasing evidence has demonstrated that heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, exhibiting cytoprotective, antioxidant, and anti-inflammatory abilities. Previously, we prepared a series of novel active halophenols possessing strong antioxidant activities in vitro and in vivo. In the present study, we demonstrated that these halophenols exhibited significant protective effects against H2O2-induced injury in EA.hy926 cells by inhibition of apoptosis and ROS and TNF-αproduction, as well as induction of the upregulation of HO-1, the magnitude of which correlated with their cytoprotective actions. Further experiments which aimed to determine the mechanistic basis of these actions indicated that the halophenols induced the activation of Nrf2, Erk1/2, and PI3K/Akt without obvious effects on the phosphorylation of p38, JNK, or the expression of PKC-δ. This was validated with the use of PD98059 and Wortmannin, specific inhibitors of Erk1/2 and PI3K, respectively. Overall, our study is the first to demonstrate that the cytoprotective actions of halophenols involve their antiapoptotic, antioxidant, and anti-inflammatory abilities, which are mediated by the upregulation of Nrf2-dependent HO-1 expression and reductions in ROS and TNF-αgeneration via the activation of Erk1/2 and PI3K/Akt in EA.hy926 cells. HO-1 may thus be an important potential target for further research into the cytoprotective actions of halophenols.

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Melatonin Alleviates Contrast-Induced Acute Kidney Injury by Activation of Sirt3

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6668887 ◽

2021 ◽

Vol 2021 ◽

pp. 1-21

Author(s):

Chunmei Zhang ◽

Mengying Suo ◽

Lingxin Liu ◽

Yan Qi ◽

Chen Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Transforming Growth Factor ◽

Kidney Injury ◽

Transforming Growth Factor Β ◽

Activity Levels ◽

Protective Effects ◽

Melatonin Treatment

Oxidative stress and apoptosis play a vital role in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). The purpose of our study was to investigate the protective effects and mechanisms of melatonin against CI-AKI in a CI-AKI mouse model and NRK-52E cells. We established the CI-AKI model in mice, and the animals were pretreated with melatonin (20 mg/kg). Our results demonstrated that melatonin treatment exerted a renoprotective effect by decreasing the level of serum creatinine (SCr) and blood urea nitrogen (BUN), lessening the histological changes of renal tubular injuries, and reducing the expression of neutrophil gelatinase-associated lipid (NGAL), a marker of kidney injury. We also found that pretreatment with melatonin remarkably increased the expression of Sirt3 and decreased the ac-SOD2 K68 level. Consequently, melatonin treatment significantly decreased the oxidative stress by reducing the Nox4, ROS, and malondialdehyde (MDA) content and by increasing the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity levels. The antiapoptotic effect of melatonin on CI-AKI was revealed by decreasing the ratio of Bax/Bcl2 and the cleaved caspase3 level and by reducing the number of apoptosis-positive tubular cells. In addition, melatonin treatment remarkably reduced the inflammatory cytokines of interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and transforming growth factor β (TGFβ) in vivo and in vitro. Sirt3 deletion and specific Sirt3 siRNA abolished the above renoprotective effects of melatonin in mice with iohexol-induced acute kidney injury and in NRK-52E cells. Thus, our results demonstrated that melatonin exhibited the renoprotective effects of antioxidative stress, antiapoptosis, and anti-inflammation by the activation of Sirt3 in the CI-AKI model in vivo and in vitro. Melatonin may be a potential drug to ameliorate CI-AKI in clinical practice.

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The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

International Journal of Molecular Sciences ◽

10.3390/ijms20205238 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5238 ◽

Cited By ~ 12

Author(s):

Daniela Maria Tanase ◽

Evelina Maria Gosav ◽

Smaranda Radu ◽

Claudia Florida Costea ◽

Manuela Ciocoiu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

In Vivo Studies ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Induced Apoptosis ◽

Kidney Injury Molecule 1

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

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Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation

Cell Death and Disease ◽

10.1038/s41419-019-1998-y ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 3

Author(s):

Dongdong Yuan ◽

Xiaoyun Li ◽

Chenfang Luo ◽

Xianlong Li ◽

Nan Cheng ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Transplantation ◽

Acute Kidney Injury ◽

Kidney Injury ◽

Protective Effects ◽

Sprague Dawley ◽

Organ Protection ◽

Cx43 Expression

Abstract Postoperative acute kidney injury (AKI) is a severe complication after liver transplantation (LT). Its deterioration and magnification lead to the increase in mortality. Connexin43 (Cx43) mediates direct transmission of intracellular signals between neighboring cells, always considered to be the potent biological basis of organ damage deterioration and magnification. Thus, we explored the effects of Cx43 on AKI following LT and its related possible mechanism. In this study, alternations of Cx43 expression were observed in 82 patients, receiving the first-time orthotopic LT. We built autologous orthotopic liver transplantation (AOLT) models with Sprague–Dawley (SD) rats in vivo, and hypoxia-reoxygenation (H/R) or lipopolysaccharide (LPS) pretreatment models with kidney tubular epithelial cells (NRK-52E) in vitro, both of which were the most important independent risk factors of AKI following LT. Then, different methods were used to alter the function of Cx43 channels to determine its protective effects on AKI. The results indicated that patients with AKI suffering from longer time of tracheal intubation or intensive care unit stay, importantly, had significantly lower survival rate at postoperative 30 days and 3 years. In rat AOLT models, as Cx43 was inhibited with heptanol, postoperative AKI was attenuated significantly. In vitro experiments, downregulation of Cx43 with selective inhibitors, or siRNA protected against post-hypoxic NRK-52E cell injuries caused by H/R and/or LPS, while upregulation of Cx43 exacerbated the above-mentioned cell injuries. Of note, alternation of Cx43 function regulated the content of reactive oxygen species (ROS), which not only mediated oxidative stress and inflammation reactions effectively, but also regulated necroptosis. Therefore, we concluded that Cx43 inhibition protected against AKI following LT through attenuating ROS transmission between the neighboring cells. ROS alternation depressed oxidative stress and inflammation reaction, which ultimately reduced necroptosis. This might offer new insights for targeted intervention for organ protection in LT, or even in other major surgeries.

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Platelet-rich Plasma Enhanced MSCs Repair for Glycerin-induced Acute Kidney Injury via AKT/Rab27 Paracrine Pathway

10.21203/rs.3.rs-33696/v1 ◽

2020 ◽

Author(s):

Cheng Ji ◽

Jiahui Zhang ◽

Hui Shi ◽

wanzhu Liu ◽

Fengtian Sun ◽

...

Keyword(s):

Stem Cells ◽

Acute Kidney Injury ◽

Mesenchymal Stem Cells ◽

Renal Function ◽

Platelet Rich Plasma ◽

Kidney Injury ◽

Human Umbilical Cord ◽

Tubular Cells ◽

Renal Tubular Cells

Abstract Background: Acute kidney injury (AKI) was defined by rapid deterioration of renal function, as a common complication in hospitalized patients. Among the recent therapeutic options, mesenchymal stem cells (MSCs) were considered a promising strategy for damaged tissues repair. Platelet rich plasma (PRP) regulates stromal cells to repair tissue damage through the release of growth factors. Here we proposed a possible therapeutic use of human umbilical cord mesenchymal stem cells stimulated by platelet-rich plasma (PRP-MSCs) in a murine model of acute renal injury generated by glycerin injection.Methods: In vivo, we constructed cisplatin-induced acute kidney injury rat models. On day 1 post injury, rat received a tail vein injection of 1×106 MSCs and 1×106 PRP-MSCs. All animals were sacrificed at Day 3 after glycerin injection. Renal function (serum BUN, Creatinine), histopathological structure changes and tubular cells apoptosis were evaluated. In vitro experiment, 50 μmol/L of glycerin treated NRK-52E for 12h were incubated with MSC or PRP-MSC for 24h in transwell co-culture system. Cells were harvested for apoptosis assay, immunofluorescence assay, western blot, and quantitative real-time polymerase chain reaction (qRT-PCR).Results: In vivo and vitro studies confirmed that the PRP induced YAP nucleus expression to promoting the proliferation and reinforces the stemness of MSCs, and stimulated the paracrine exosomes of MSCs by activating AKT/Rab27 signaling pathway to inhibiting the apoptosis of renal tubular cells. Conclusions: Our results revealed a novel potential use of PRP-MSCs as therapeutic strategy for acute kidney injury, highlighting the presence and role of the reno-protective factor PRP-MSCs.

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Isoliquiritigenin attenuates LPS-induced acute kidney injury through suppression of HMGB1 pathway in renal tubular against ferritinophagy

10.21203/rs.2.24196/v1 ◽

2020 ◽

Author(s):

Yun Tang ◽

Yanmei Wang ◽

Chan Wang ◽

Meidie Yu ◽

Li Li ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Dysfunction ◽

Kidney Injury ◽

Tubular Injury ◽

Renal Tubular Cells ◽

Septic Acute Kidney Injury ◽

Life Threatening ◽

Renal Tubular

Abstract Septic acute kidney injury (AKI) mainly results in life-threatening renal dysfunction involving renal tubular injury to bring heavy burden to patients in intensive care unit (ICU). However, there is still a lack of therapy to prevent septic AKI effectively and inexpensive. To observe the role and novel mechanism of isoliquiritigenin (ISL) which isolated from the roots of licorice in septic AKI, we used LPS to induce renal tubular injury upon septic AKI both in vitro and in vivo. 50mg/kg ISL and 5 mg/kg Ferrostatin-1 were once given to the male C57BL/6 mice one hour before 1 mg/kg LPS i.p injection. 50 μM and 100 μM ISL respectively pre-treat the human renal tubular cells 5 hrs before 2 μg/ml LPS stimulation. We found ISL pretreatment apparently reversed LPS-induced renal dysfunction and ameliorated murine renal tubular injury by suppression HMGB1 pathway. Furthermore, we observed that LPS induced autophagy and ferroptosis in renal tubular, whereas ISL pretreatment significantly suppress autophagy and ferroptosis of renal tubular both in vitro and in vivo. Mechanically, autophagy activated ferroptosis via NCOA4-mediated ferritinophagy. Moreover, HMGB1 is required for ferritinophagy in renal tubular. ISL treatment inhibited the expression of HMGB1. Taken together, these results suggest that ISL protects LPS-induced acute kidney injury through suppression of HMGB1 pathway in renal tubular against ferritinophagy.

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Uremia induces proximal tubular cytoresistance and heme oxygenase-1 expression in the absence of acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.90645.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. F362-F368 ◽

Cited By ~ 10

Author(s):

Richard A. Zager

Keyword(s):

Acute Kidney Injury ◽

Heme Oxygenase ◽

Stress Responses ◽

Injury Severity ◽

Protective Action ◽

Kidney Injury ◽

Heme Oxygenase 1 ◽

Heat Labile ◽

Proximal Tubular

Acute kidney injury (AKI) induces adaptive responses within proximal tubular (PT) cells that serve to protect them from further ischemic or toxic damage. However, it is not known whether uremia, a potential consequence of AKI, independently alters susceptibility to tubular injury. To address this issue, we subjected CD-1 mice to bilateral ureteral transection (BUTx), which produces uremia (blood urea nitrogen ∼150 mg/dl) in the absence of direct renal damage. PT segments were then isolated from BUTx and control mice and subjected to in vitro hypoxic injury. Additionally, “in vitro uremia” was modeled in isolated tubules or in cultured PT (HK-2) cells by addition of 1) peritoneal dialysate (obtained from mice with bilateral ureteral obstruction), 2) peritoneal fluid (from BUTx mice), or 3) normal human urine (pH 7.4, with and without boiling). Effects on injury severity (lactate dehydrogenase release) were assessed. Finally, because uremia is a prooxidant state, it was hypothesized that BUTx would increase renal lipid peroxidation (malondialdehyde) and induce heme oxygenase-1 (HO-1), a redox-sensitive cytoprotective protein. BUTx conferred striking protection against hypoxic damage. This could be partially modeled in tubules and HK-2 cells by induction of in vitro uremia. Urine's protective action was heat labile (largely destroyed by boiling). BUTx caused a tripling of renal malondialdehyde and HO-1 protein levels. Increased HO-1 transcription was likely involved, as indicated by a tripling of HO-1 mRNA and RNA polymerase II binding along the HO-1 gene (chromatin immunoprecipitation assay). “Gene-activating” histone modifications [H3K4 trimethylation (H3K4m3) and histone 2 variant (H2A.Z)] at HO-1 gene loci were also observed. Uremia, per se, can contribute to the AKI-induced cytoresistance. Low-molecular-weight, heat-labile, cytoprotective factor(s) and uremia-induced renal stress responses (e.g., HO-1 gene activation) are likely involved. Finally, renal HO-1 induction following AKI may reflect direct cell injury effects and adaptations to uremia.

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