TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury

2018 ◽  
Vol 132 (16) ◽  
pp. 1725-1739 ◽  
Author(s):  
Magaiver Andrade-Silva ◽  
Marcos Antonio Cenedeze ◽  
Luiz Augusto Perandini ◽  
Raphael José Ferreira Felizardo ◽  
Ingrid Kazue Mizuno Watanabe ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Protective Role ◽  
Heme Oxygenase 1 ◽  
Protective Function ◽  
Autophagy Induction ◽  
Lower Expression

Acute kidney injury (AKI) is considered an inflammatory disease in which toll-like receptors (TLRs) signaling pathways play an important role. The activation of TLRs results in production of several inflammatory cytokines leading to further renal damage. In contrast, TLRs are key players on autophagy induction, which is associated with a protective function on cisplatin-induced AKI. Hence, the present study aimed to evaluate the specific participation of TLR2 and TLR4 molecules on the development of cisplatin-induced AKI. Complementarily, we also investigated the link between TLRs and heme oxygenase-1 (HO-1), a promisor cytoprotective molecule. First, we observed that only the absence of TLR2 but not TLR4 in mice exacerbated the renal dysfunction, tissue injury and mortality rate, even under an immunologically privileged microenvironment. Second, we demonstrated that TLR2 knockout (KO) mice presented lower expression of autophagy-associated markers when compared with TLR4 KO animals. Similar parameter was confirmed in vitro, using tubular epithelial cells derived from both KO mice. To test the cross-talking between HO-1 and TLRs, hemin (an HO-1 internal inducer) was administrated in cisplatin-treated TLR2 and TLR4 KO mice and it was detected an improvement in the global renal tissue parameters. However, this protection was less evident at TLR2 KO mice. In summary, we documented that TLR2 plays a protective role in cisplatin-induced AKI progression, in part, by a mechanism associated with autophagy up-regulation, considering that its interplay with HO-1 can promote renal tissue recover.

scholarly journals SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Zhiya Deng ◽  
Maomao Sun ◽  
Jie Wu ◽  
Haihong Fang ◽  
Shumin Cai ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protective Effect ◽  
Cell Model ◽  
Kidney Injury ◽  
Underlying Mechanism ◽  
Autophagy Induction ◽  
Promising Therapeutic Approach ◽  
Related Proteins ◽  
Caecal Ligation And Puncture

AbstractOur previous studies showed that silent mating-type information regulation 2 homologue-1 (SIRT1, a deacetylase) upregulation could attenuate sepsis-induced acute kidney injury (SAKI). Upregulated SIRT1 can deacetylate certain autophagy-related proteins (Beclin1, Atg5, Atg7 and LC3) in vitro. However, it remains unclear whether the beneficial effect of SIRT1 is related to autophagy induction and the underlying mechanism of this effect is also unknown. In the present study, caecal ligation and puncture (CLP)-induced mice, and an LPS-challenged HK-2 cell line were established to mimic a SAKI animal model and a SAKI cell model, respectively. Our results demonstrated that SIRT1 activation promoted autophagy and attenuated SAKI. SIRT1 deacetylated only Beclin1 but not the other autophagy-related proteins in SAKI. SIRT1-induced autophagy and its protective effect against SAKI were mediated by the deacetylation of Beclin1 at K430 and K437. Moreover, two SIRT1 activators, resveratrol and polydatin, attenuated SAKI in CLP-induced septic mice. Our study was the first to demonstrate the important role of SIRT1-induced Beclin1 deacetylation in autophagy and its protective effect against SAKI. These findings suggest that pharmacologic induction of autophagy via SIRT1-mediated Beclin1 deacetylation may be a promising therapeutic approach for future SAKI treatment.

scholarly journals Gene Microarray Integrated with High-Throughput Proteomics for the Discovery of Transthyretin in Rhabdomyolysis-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (4) ◽  
pp. 1673-1688 ◽  
Author(s):  
Ou Li ◽  
Xiaodong Geng ◽  
Qian Ma ◽  
Weiwei Wang ◽  
Ran Liu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Western Blotting ◽  
Kidney Injury ◽  
Physical Exertion ◽  
Renal Tissue ◽  
Gene Microarray ◽  
Absolute Quantitation ◽  
Gene And Protein Expression ◽  
Isobaric Tagging

Background/Aims: Rhabdomyolysis, one of the leading causes of acute kidney injury (AKI), develops after trauma, drug toxicity, infections, burns, and physical exertion. The aim of this study was to investigate differences in gene and protein expression to elucidate the pathogenesis of rhabdomyolysis (RM)-induced AKI. Methods: In this study, we used glycerol induced renal injury as a model of RM-induced AKI. Affymetrix U133 plus 2.0 microarrays were used to perform gene microarray analysis. Isobaric tagging with related and absolute quantitation (iTRAQ) labeling mass spectrometry (MS) was applied to screen and identify differentially expressed proteins between RM-induced AKI and normal murine renal tissue. Verification experiments included immunohistochemistry (IHC), real-time PCR, Western blotting, and the measurement of ATP and ROS production. HK-2 cells were incubated in vitro with ferrous myoglobin and pcDNA-TTR, followed by assays to detect cell proliferation, ROS and apoptosis. Results: According to gene microarray and iTRAQ-MS analysis, we screened 17 common elements. After multiple analyses, we selected transthyretin (TTR) as our focus and investigated TTR in the kidney. Verification experiments with IHC confirmed differential expression levels of TTR proteins. Furthermore, Western blotting showed a stepwise decrease in TTR in AKI renal tissues. Cell-based experiments showed that overexpression of TTR could improve HK-2 cell viability and inhibit apoptosis. TTR reduced apoptosis by decreasing the accumulation of reactive oxygen species (ROS). Conclusion: This study reports a possible mechanism for RM-induced AKI and suggests that reductions in TTR could increase the generation of ROS and induce apoptosis. TTR may be a potentially valuable target for RM-induced AKI.

scholarly journals Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5717 ◽  
Author(s):  
Jung-Yeon Kim ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Anti Inflammatory

Sepsis is the major cause of acute kidney injury (AKI) in severely ill patients, but only limited therapeutic options are available. During sepsis, lipopolysaccharide (LPS), an endotoxin derived from bacteria, activates signaling cascades involved in inflammatory responses and tissue injury. Apamin is a component of bee venom and has been shown to exert antioxidative, antiapoptotic, and anti-inflammatory activities. However, the effect of apamin on LPS-induced AKI has not been elucidated. Here, we show that apamin treatment significantly ameliorated renal dysfunction and histological injury, especially tubular injury, in LPS-injected mice. Apamin also suppressed LPS-induced oxidative stress through modulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and heme oxygenase-1. Moreover, tubular cell apoptosis with caspase-3 activation in LPS-injected mice was significantly attenuated by apamin. Apamin also inhibited cytokine production and immune cell accumulation, suppressed toll-like receptor 4 pathway, and downregulated vascular adhesion molecules. Taken together, these results suggest that apamin ameliorates LPS-induced renal injury through inhibiting oxidative stress, apoptosis of tubular epithelial cells, and inflammation. Apamin might be a potential therapeutic option for septic AKI.

Troxerutin down-regulates KIM-1, modulates p38 MAPK signaling, and enhances renal regenerative capacity in a rat model of gentamycin-induced acute kidney injury

2018 ◽  
Vol 9 (12) ◽  
pp. 6632-6642 ◽  
Author(s):  
Samir A. Salama ◽  
Hany H. Arab ◽  
Ibrahim A. Maghrabi
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
P38 Mapk ◽  
Tissue Regeneration ◽  
Rat Model ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Mapk Signaling ◽  
Regenerative Capacity

Troxerutin enhances renal tissue regeneration, improves renal function, and decreases renal tissue injury in gentamycin-treated rats.

scholarly journals Involvement of S100A8/A9-TLR4-NLRP3 Inflammasome Pathway in Contrast-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (1) ◽  
pp. 209-222 ◽  
Author(s):  
Xuexian Tan ◽  
Xiaohe Zheng ◽  
Zena Huang ◽  
Jiaqiong Lin ◽  
Chuli Xie ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Nlrp3 Inflammasome ◽  
Tissue Injury ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Underlying Mechanism ◽  
Male Rats ◽  
Ros Generation

Background: Contrast-induced acute kidney injury (CIAKI) is a common cause of hospital-acquired acute kidney injury (AKI). S100A8/A9-TLR4-NLRP3 inflammasome pathway triggers inflammation, apoptosis and tissue injury in several AKI models. Nevertheless, the underlying mechanism of S100A8/A9-TLR4-NLRP3 inflammasome pathway in CIKAI is not clear. We aimed to investigate the possible role of S100A8/A9-TLR4-NLRP3 inflammasome in the pathophysiology of CIAKI. Methods: We treated male rats and NRK-52E cells by iopromide to establish in vivo and in vitro models of CIAKI. We collected serum and urine samples to detect renal function. We obtained kidney tissue for histological analysis and detection of protein concentration. We used inhibitor of TLR4 and NLRP3-siRNA to further testify their role in CIAKI in NRK-52E cells. Results: Iopromide caused elevation of SCr, BUN and NGAL level, decrease of endogenous creatinine clearance, morphological injury and tubular apoptosis, enhanced IL-1β and IL-18 expression, and increased expression of S100A8/A9, TLR4 and NLRP3 inflammsome. In NRK-52E cells, iopromide caused enhanced apoptotic rates and ROS generation, which could be ameliorated by inhibitor of TLR4 and NLRP3-siRNA. Moreover, inhibition of TLR4 dampened NLRP3 expression. Conclusion: S100A8/A9-TLR4-NLRP3 inflammasome pathway represented a key mechanism of CI-AKI, which provided a potential therapeutic target.

scholarly journals Protective role of DJ-1 in endotoxin-induced acute kidney injury

2020 ◽  
Vol 319 (4) ◽  
pp. F654-F663 ◽  
Author(s):  
Joseph Leeds ◽  
Yogesh Scindia ◽  
Valentina Loi ◽  
Ewa Wlazlo ◽  
Elizabeth Ghias ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Collecting Duct ◽  
Kidney Injury ◽  
Protective Role ◽  
In Vivo Model ◽  
Renal Tubules ◽  
Death Domain ◽  
Renal Tubular

Acute kidney injury (AKI) is a frequent complication of sepsis and an important cause of morbidity and mortality worldwide. A cornerstone of sepsis-associated AKI is dysregulated inflammation, leading to increased tissue oxidative stress and free radical formation, which leads to multiple forms of cell death. DJ-1 is a peroxiredoxin protein with multiple functions, including its ability to control cellular oxidative stress. Although DJ-1 is expressed prominently by renal tubules, its role in AKI has not been investigated. In the present study, we examined the effect of DJ-1 deficiency in a murine model of endotoxin-induced AKI. Endotoxemia induced greater kidney injury in DJ-1-deficient mice. Furthermore, DJ-1 deficiency increased renal oxidative stress associated with increased renal tubular apoptosis and with expression of death domain-associated protein (DAXX). Similar to the in vivo model, in vitro experiments using a medullary collecting duct cell line (mIMCD3) and cytotoxic serum showed that serum obtained from wild-type mice resulted in increased expression of s100A8/s100A9, DAXX, and apoptosis in DJ-1-deficient mIMCD3 cells. Our findings demonstrate a novel renal protective role for renal tubular DJ-1 during endotoxemia through control of oxidative stress, renal inflammation, and DAXX-dependent apoptosis.

scholarly journals Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats

Antioxidants ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 430 ◽  
Author(s):  
Saleem H. Aladaileh ◽  
Omnia E. Hussein ◽  
Mohammad H. Abukhalil ◽  
Sultan A. M. Saghir ◽  
May Bin-Jumah ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Antioxidant Defenses ◽  
Heme Oxygenase 1 ◽  
Caspase 9 ◽  
Tnf Α ◽  
Cox 2 ◽  
Kidney Injury Molecule 1

Acute kidney injury (AKI) is a serious complication of methotrexate (MTX). This study explored the protective effect of the isoflavone formononetin (FN) against MTX nephrotoxicity with an emphasis on oxidative stress, inflammation, and nuclear factor (erythroid-derived 2)-like 2/heme oxygenase 1 (Nrf2/HO-1) signaling. Rats received FN (10, 20, and 40 mg/kg) for 10 days and a single dose of MTX on day 7. MTX induced kidney injury was characterized by increased serum creatinine and urea, kidney injury molecule-1 (Kim-1), and several histological alterations. FN ameliorated kidney function and inhibited the renal tissue injury induced by MTX. Reactive oxygen species (ROS), lipid peroxidation (LPO), nitric oxide, and 8-Oxo-2′-deoxyguanosine were increased, whereas antioxidant defenses were diminished in the kidney of MTX-administered rats. In addition, MTX upregulated renal iNOS, COX-2, TNF-α, IL-1β, Bax, caspase-9, and caspase-3, and decreased Bcl-2, Nrf2, and HO-1. FN suppressed oxidative stress, LPO, DNA damage, iNOS, COX-2, proinflammatory cytokines, and apoptosis, and boosted Bcl-2, antioxidants, and Nrf2/HO-1 signaling in MTX-administered rats. In conclusion, FN prevents MTX-induced AKI by activating Nrf2/HO-1 signaling and attenuates oxidative damage and inflammation. Thus, FN may represent an effective adjuvant that can prevent MTX nephrotoxicity, pending further mechanistic studies.

scholarly journals Cyclophilin A Promotes Inflammation in Acute Kidney Injury but Not in Renal Fibrosis

2020 ◽  
Vol 21 (10) ◽  
pp. 3667
Author(s):  
Khai Gene Leong ◽  
Elyce Ozols ◽  
John Kanellis ◽  
David J. Nikolic-Paterson ◽  
Frank Y. Ma
Keyword(s):  
Acute Kidney Injury ◽  
Mammalian Cells ◽  
Tissue Injury ◽  
Interstitial Fibrosis ◽  
Cell Damage ◽  
Kidney Injury ◽  
Cyclophilin A ◽  
Iri Model ◽  
Ischaemia Reperfusion Injury

Cyclophilin A (CypA) is a highly abundant protein in the cytoplasm of most mammalian cells. Beyond its homeostatic role in protein folding, CypA is a Damage-Associated Molecular Pattern which can promote inflammation during tissue injury. However, the role of CypA in kidney disease is largely unknown. This study investigates the contribution of CypA in two different types of kidney injury: acute tubular necrosis and progressive interstitial fibrosis. CypA (Ppia) gene deficient and wild type (WT) littermate controls underwent bilateral renal ischaemia/reperfusion injury (IRI) and were killed 24 h later or underwent left unilateral ureteric obstruction (UUO) and were killed 7 days later. In the IRI model, CypA−/− mice showed substantial protection against the loss of renal function and from tubular cell damage and death. This was attributed to a significant reduction in neutrophil and macrophage infiltration since CypA−/− tubular cells were not protected from oxidant-induced cell death in vitro. In the UUO model, CypA−/− mice were not protected from leukocyte infiltration or renal interstitial fibrosis. In conclusion, CypA promotes inflammation and acute kidney injury in renal IRI, but does not contribute to inflammation or interstitial fibrosis in a model of progressive kidney fibrosis.

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

2011 ◽  
Vol 301 (1) ◽  
pp. F162-F170 ◽  
Author(s):  
Qingqing Wei ◽  
William D. Hill ◽  
Yunchao Su ◽  
Shuang Huang ◽  
Zheng Dong
Keyword(s):  
Acute Kidney Injury ◽  
Heme Oxygenase ◽  
Cell Injury ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Tubular Cells ◽  
Renal Tubular Cells

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.

scholarly journals Red blood cell antibody-induced anemia causes differential degrees of tissue hypoxia in kidney and brain

2018 ◽  
Vol 314 (4) ◽  
pp. R611-R622 ◽  
Author(s):  
Nikhil Mistry ◽  
C. David Mazer ◽  
John G. Sled ◽  
Alan H. Lazarus ◽  
Lindsay S. Cahill ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Blood Flow ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Tissue Hypoxia ◽  
Heme Oxygenase 1 ◽  
Cerebral Tissue

Moderate anemia is associated with increased mortality and morbidity, including acute kidney injury (AKI), in surgical patients. A red blood cell (RBC)-specific antibody model was utilized to determine whether moderate subacute anemia could result in tissue hypoxia as a potential mechanism of injury. Cardiovascular and hypoxic cellular responses were measured in transgenic mice capable of expressing hypoxia-inducible factor-1α (HIF-1α)/luciferase activity in vivo. Antibody-mediated anemia was associated with mild intravascular hemolysis (6 h) and splenic RBC sequestration ( day 4), resulting in a nadir hemoglobin concentration of 89 ± 13 g/l on day 4. At this time point, renal tissue oxygen tension (PtO2) was decreased in anemic mice relative to controls (13.1 ± 4.3 vs. 20.8 ± 3.7 mmHg, P < 0.001). Renal tissue hypoxia was associated with an increase in HIF/luciferase expression in vivo ( P = 0.04) and a 20-fold relative increase in renal erythropoietin mRNA transcription ( P < 0.001) but no increase in renal blood flow ( P = 0.67). By contrast, brain PtO2 was maintained in anemic mice relative to controls (22.7 ± 5.2 vs. 23.4 ± 9.8 mmHg, P = 0.59) in part because of an increase in internal carotid artery blood flow (80%, P < 0.001) and preserved cerebrovascular reactivity. Despite these adaptive changes, an increase in brain HIF-dependent mRNA levels was observed (erythropoietin: P < 0.001; heme oxygenase-1: P = 0.01), providing evidence for subtle cerebral tissue hypoxia in anemic mice. These data demonstrate that moderate subacute anemia causes significant renal tissue hypoxia, whereas adaptive cerebrovascular responses limit the degree of cerebral tissue hypoxia. Further studies are required to assess whether hypoxia is a mechanism for acute kidney injury associated with anemia.

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