Curcumin and enalapril ameliorate renal failure by antagonizing inflammation in ⅚ nephrectomized rats: role of phospholipase and cyclooxygenase

Previously, we showed that curcumin prevents chronic kidney disease (CKD) development in ⅚ nephrectomized (Nx) rats when given within 1 wk after Nx (Ghosh SS, Massey HD, Krieg R, Fazelbhoy ZA, Ghosh S, Sica DA, Fakhry I, Gehr TW. Am J Physiol Renal Physiol 296: F1146–F1157, 2009). To better mimic the scenario for renal disease in humans, we began curcumin and enalapril therapy when proteinuria was already established. We hypothesized that curcumin, by blocking the inflammatory mediators TNF-α and IL-1β, could also reduce cyclooxygenase (COX) and phospholipase expression in the kidney. Nx animals were divided into untreated Nx, curcumin-treated, and enalapril-treated groups. Curcumin (75 mg/kg) and enalapril (10 mg/kg) were administered for 10 wk. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was comparably reduced by curcumin and enalapril, with only enalapril significantly lowering blood pressure. Compared with controls, Nx animals had higher plasma/kidney TNF-α and IL-1β, which were reduced by curcumin and enalapril treatment. Nx animals had significantly elevated kidney levels of cytosolic PLA2, calcium-independent intracellular PLA2, COX 1, and COX 2, which were comparably reduced by curcumin and enalapril. Studies in mesangial cells and macrophages were carried out to establish that the in vivo increase in PLA2 and COX were mediated by TNF-α and IL-1β and that curcumin, by antagonizing the cytokines, could significantly reduce both PLA2 and COX. We conclude that curcumin ameliorates CKD by blocking inflammatory signals even if it is given at a later stage of the disease.

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Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation

AJP Renal Physiology ◽

10.1152/ajprenal.90732.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. F1146-F1157 ◽

Cited By ~ 82

Author(s):

S. S. Ghosh ◽

H. D. Massey ◽

R. Krieg ◽

Z. A. Fazelbhoy ◽

S. Ghosh ◽

...

Keyword(s):

Renal Failure ◽

Mesangial Cells ◽

Nitrogen Plasma ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Peroxisome Proliferator Activated Receptor ◽

Tnf Α ◽

Anti Inflammatory ◽

Enalapril Treatment

TNF-α and NF-κB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-α-elicited NF-κB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-α, which was associated with NF-κB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor γ (PPARγ) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-α. Curcumin dose dependently antagonized the TNF-α-mediated decrease in PPARγ and blocked transactivation of NF-κB and repression of PPARγ, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.

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MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

Bioscience Reports ◽

10.1042/bsr20200527 ◽

2020 ◽

Vol 40 (6) ◽

Author(s):

Xudong Wang ◽

Yali Wang ◽

Mingjian Kong ◽

Jianping Yang

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Response ◽

Periodic Acid ◽

Kidney Injury ◽

Luciferase Reporter ◽

Tunel Staining ◽

Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

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TNF-α and myocardial depression in endotoxemic rats: temporal discordance of an obligatory relationship

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.2.r502 ◽

1998 ◽

Vol 275 (2) ◽

pp. R502-R508 ◽

Cited By ~ 13

Author(s):

Xianzhong Meng ◽

Lihua Ao ◽

Daniel R. Meldrum ◽

Brian S. Cain ◽

Brian D. Shames ◽

...

Keyword(s):

Temporal Relationship ◽

Contractile Function ◽

Myocardial Depression ◽

Tnf Α ◽

Myocardial Contractile ◽

Factor Α ◽

Relationship Of

Exogenous tumor necrosis factor-α (TNF-α) induces delayed myocardial depression in vivo but promotes rapid myocardial depression in vitro. The temporal relationship between endogenous TNF-α and endotoxemic myocardial depression is unclear, and the role of TNF-α in this myocardial disorder remains controversial. Using a rat model of endotoxemia not complicated by shock, we sought to determine 1) the temporal relationship of changes in circulating and myocardial TNF-α with myocardial depression, 2) the influences of protein synthesis inhibition or immunosuppression on TNF-α production and myocardial depression, and 3) the influence of neutralization of TNF-α on myocardial depression. Rats were treated with lipopolysaccharide (LPS, 0.5 mg/kg ip). Circulating and myocardial TNF-α increased at 1 and 2 h, whereas myocardial contractility was depressed at 4 and 6 h. Pretreatment with cycloheximide or dexamethasone abolished the increase in circulating and myocardial TNF-α and preserved myocardial contractile function. Similarly, treatment with TNF binding protein immediately after LPS prevented myocardial depression. We conclude that endogenous TNF-α mediates delayed myocardial depression in endotoxemic rats and that inhibition of TNF-α production or neutralization of TNF-α preserves myocardial contractile function in endotoxemia.

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HIF-1α contributes to Ang II-induced inflammatory cytokine production in podocytes

BMC Pharmacology and Toxicology ◽

10.1186/s40360-019-0340-8 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 4

Author(s):

Hao Huang ◽

Yanqin Fan ◽

Zhao Gao ◽

Wei Wang ◽

Ning Shao ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Renin Angiotensin System ◽

Inflammatory Factors ◽

Ang Ii ◽

Angiotensin System ◽

Inflammatory Injury ◽

Tnf Α

Abstract Background Studies have indicated that changed expression of hypoxia-inducible factor-1α (HIF-1α) in epithelial cells from the kidney could affect the renal function in chronic kidney disease (CKD). As Angiotensin II (Ang II) is a critical active effector in the renin-angiotensin system (RAS) and was proved to be closely related to the inflammatory injury. Meanwhile, researchers found that Ang II could alter the expression of HIF-1α in the kidney. However, whether HIF-1α is involved in mediating Ang II-induced inflammatory injury in podocytes is not clear. Methods Ang II perfusion animal model were established to assess the potential role of HIF-1α in renal injury in vivo. Ang II stimulated podocytes to observe the corresponding between HIF-1α and inflammatory factors in vitro. Results The expression of inflammatory cytokines such as MCP-1 and TNF-α was increased in the glomeruli from rats treated with Ang II infusion compared with control rats. Increased HIF-1α expression in the glomeruli was also observed in Ang II-infused rats. In vitro, Ang II upregulated the expression of HIF-1α in podocytes. Furthermore, knockdown of HIF-1α by siRNA decreased the expression of MCP-1 and TNF-α. Moreover, HIF-1α siRNA significantly diminished the Ang II-induced overexpression of HIF-1α. Conclusion Collectively, our results suggest that HIF-1α participates in the inflammatory response process caused by Ang II and that downregulation of HIF-1α may be able to partially protect or reverse inflammatory injury in podocytes.

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5-LIPOXYGENASE INHIBITOR (ZILEUTON) PRODUCES ANTI-DEPRESSION EFFECT IN STRESS INDUCE CRS MICE MODEL

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2020.v13i2.36501 ◽

2019 ◽

pp. 154-162

Author(s):

SAPTARSHI PANIGRAHI ◽

SOMNATH SURAI ◽

HAO HONG

Keyword(s):

Caspase 3 ◽

Molecular Level ◽

Behavioral Tests ◽

Mice Model ◽

Lipoxygenase Inhibitor ◽

Treatment Groups ◽

Tnf Α ◽

Crs Model

Objective: The experiment aimed to find out the effectiveness of Zileuton, a 5-LOX inhibitor on depressive behavior and neuroinflammation in vivo. Method: Male ICR mice (25-30g) randomly distributed Veh+Veh, CRS+Vehicle, CRS+ZIL50, and CRS+ZIL100. Zileuton was orally given in the treatment groups for 21 days after 3 weeks of stress induce CRS model. Starting from the day 1, in CRS model, mice were immobilized 8 hr/day for consecutive 21 days to induce stress. After completing the drug administration, subjected the mice for behavioral tests, and then performed histopathological & Western Blotting. Result: Stress induces CRS model guide to the significant depressive-like behavior of the mice in behavioral tests which was united by adverse changes at the cellular/molecular level responsible for regulation of inflammatory and apoptotic processes. CRS triggered Microglial over activation in the DG of the hippocampus, which was successfully inhibited by Zileuton post-treatment at the dose of 100mg/kg than 50mg/kg. Level of TNF-α, IL- 1β, nuclear NF-κB p65, Bax, and cleaved Caspase-3 was high and Bcl-2 expression was low in the stress induce CRS -treated mice which were found to be opposite in the Zileuton (100mg/kg). However, the dose of 50mg/kg less to mimic the effects as exhibited more by the 100mg/kg dose of Zileuton. Conclusion: It can be concluded that selective 5-lipoxygenase inhibitor Zileuton can efficiently inhibit the depressive-like behavior/activity in CRS-induced depressive mouse model. The study is the first to show the role of 5-lipoxygenase enzyme in and Chronic Restraint Stress (CRS)-induced mice models of stress, anxiety or depression.

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Genetic Predisposition of the Interleukin-6 Response to Inflammation: Implications for a Variety of Major Diseases?

Clinical Chemistry ◽

10.1373/clinchem.2004.037531 ◽

2004 ◽

Vol 50 (11) ◽

pp. 2136-2140 ◽

Cited By ~ 140

Author(s):

Marie Bennermo ◽

Claes Held ◽

Sten Stemme ◽

Carl-Göran Ericsson ◽

Angela Silveira ◽

...

Keyword(s):

Interleukin 6 ◽

Promoter Region ◽

Insulin Dependent Diabetes Mellitus ◽

Juvenile Chronic Arthritis ◽

In Vivo Studies ◽

Dependent Diabetes Mellitus ◽

Tnf Α

Abstract Background: A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position −174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the −174 SNP for the induction of IL-6 in vivo. Methods: We vaccinated 20 and 18 healthy individuals homozygous for the −174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) were measured in the blood at baseline and up to 24 h after vaccination. Results: Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1β and TNF-α before or after vaccination. Conclusions: The −174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

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Microvascular Mechanisms of Polyphosphate-Induced Neutrophil-Endothelial Cell Interactions in vivo

European Surgical Research ◽

10.1159/000497435 ◽

2019 ◽

Vol 60 (1-2) ◽

pp. 53-62

Author(s):

Feifei Du ◽

Yongzhi Wang ◽

Zhiyi Ding ◽

Matthias W. Laschke ◽

Henrik Thorlacius

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Pharmacological Intervention ◽

Lymphocyte Function ◽

Microvascular Endothelium ◽

Recruitment Methods ◽

Leukocyte Accumulation ◽

Tnf Α

Background: Polyphosphates (PolyPs) have been reported to exert pro-inflammatory effects. However, the molecular mechanisms regulating PolyP-provoked tissue accumulation of leukocytes are not known. The aim of the present investigation was to determine the role of specific adhesion molecules in PolyP-mediated leukocyte recruitment. Methods: PolyPs and TNF-α were intrascrotally administered, and anti-P-selectin, anti-E-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1), and neutrophil depletion antibodies were injected intravenously or intraperitoneally. Intravital microscopy of the mouse cremaster microcirculation was used to examine leukocyte-endothelium interactions and recruitment in vivo. Results: Intrascrotal injection of PolyPs increased leukocyte accumulation. Depletion of neutrophils abolished PolyP-induced leukocyte-endothelium interactions, indicating that neutrophils were the main leukocyte subtype responding to PolyP challenge. Immunoneutralization of P-selectin and PSGL-1 abolished PolyP-provoked neutrophil rolling, adhesion, and emigration. Moreover, immunoneutralization of Mac-1 and LFA-1 had no impact on neutrophil rolling but markedly reduced neutrophil adhesion and emigration evoked by PolyPs. Conclusion: These results suggest that P-selectin and PSGL-1 exert important roles in PolyP-induced inflammatory cell recruitment by mediating neutrophil rolling. In addition, our data show that Mac-1 and LFA-1 are necessary for supporting PolyP-triggered firm adhesion of neutrophils to microvascular endothelium. These novel findings define specific molecules as potential targets for pharmacological intervention in PolyP-dependent inflammatory diseases.

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Role of interleukin-1 and tumour necrosis factor in leukocyte recruitment to acute dermal inflammation

Mediators of Inflammation ◽

10.1155/s0962935192000528 ◽

1992 ◽

Vol 1 (5) ◽

pp. 347-353 ◽

Cited By ~ 5

Author(s):

Andrew C. Issekutz ◽

Nancy Lopes ◽

Thomas B. Issekutz

Keyword(s):

Monoclonal Antibody ◽

Umbilical Vein ◽

Interleukin 1 ◽

E Coli ◽

Tnf Α ◽

Lps Activation ◽

Necrosis Factor

The cytokines IL-1 and TNF-α are involved in inflammation and their production is stimulated by various agents, especially endotoxin (LPS). Here, using the human IL-1 receptor antagonist (IL-1RA) and a new monoclonal antibody (mAb 7F11) to rabbit TNF, the role of endogenous IL-l and TNF production in acute (3h) leukocyte (PMNL) recruitment to dermal inflammation in rabbits has been studied. IL-1RA inhibited by 27% the PMNL accumulation in reactions induced by killed Escherichia coli (p < 0.05) but not by LPS. The monoclonal antibody to TNF inhibited by 27% and 38% (p < 0.002) the PMNL accumulation in LPS and E. coli reactions respectively, but a combination of the mAb with IL-1RA was not more effective. Treatment of human umbilical vein endothelium with LPS for 3 h activated endothelium to induce PMNL transendothelial migration in vitro, which was not inhibited by IL-1RA, antibody to TNF-α, IL-1 or to IL-8. In conclusion, TNF and IL-1 may partially mediate acute PMNL infiltration in vivo to LPS and Gram negative bacteria, but there is a major IL-1/TNF independent mechanism, at least in dermal inflammation, which may be due to direct LPS activation of the microvasculature or perhaps the generation of cytokines other than IL-1 and TNF.

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