Low-dose carvedilol protects against acute septic renal injury in rats during the early and late phases

2015 ◽  
Vol 93 (6) ◽  
pp. 443-450 ◽  
Author(s):  
Hala Salah Abdel kawy
Keyword(s):  
Renal Injury ◽  
Cecal Ligation ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Serum Levels ◽  
Renal Perfusion ◽  
Protein Carbonyls ◽  
Necrosis Factor Alpha ◽  
Inflammatory Parameters ◽  
The Impact

Recent findings from septic acute renal injury studies have implicated the mitochondrion as an important factor in kidney injury, and that increased sympathetic nerve activity may contribute to the induction of organ failure. This study investigated the impact of a nondepressor dose of carvedilol, which is a beta-adrenoreceptor antagonist with antioxidant activity, on septic renal injury induced in rats with cecal ligation and puncture (CLP). Three groups of rats were studied. The first group was the sham-operated control. The other 2 groups of rats underwent CLP, and were administered either the vehicle or carvedilol (2.0 mg/kg body mass, by intraperitoneal (i.p.) injection, daily for 2 days as well as 30 min prior to CLP). Kidney function, inflammatory parameters, mitochondrial function, and renal perfusion pressure (RPP) were investigated at 6 and 18 h after CLP. Carvedilol did not significantly induce hypotension, and it significantly improved RPP and renal dysfunction induced with CLP, together with significant reductions in serum levels of interleukin 6 and tumor necrosis factor-alpha. Septic kidney injury mediated increased levels of malondialdehyde and protein carbonyls. Carvedilol also attenuated the decrease in kidney mitochondrial glutathione and nicotinamide adenine dinucleotide phosphate dehydrogenase. Further, intracellular renal edema and inflammation induced with CLP were reduced with carvedilol. These findings suggest renoprotective effects of carvedilol in sepsis.

scholarly journals Kahweol Ameliorates Cisplatin-Induced Acute Kidney Injury through Pleiotropic Effects in Mice

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 572
Author(s):  
Jung-Yeon Kim ◽  
Jungmin Jo ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Renal Injury ◽  
Manganese Superoxide Dismutase ◽  
Immune Cell ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Pleiotropic Effects ◽  
Induced Apoptosis ◽  
Vascular Adhesion

Cisplatin is an effective chemotherapeutic agent, but its clinical use is frequently limited by its nephrotoxicity. The pathogenesis of cisplatin-induced acute kidney injury (AKI) remains incompletely understood, but oxidative stress, tubular cell death, and inflammation are considered important contributors to cisplatin-induced renal injury. Kahweol is a natural diterpene extracted from coffee beans and has been shown to possess anti-oxidative and anti-inflammatory properties. However, its role in cisplatin-induced nephrotoxicity remains undetermined. Therefore, we investigated whether kahweol exerts a protective effect against cisplatin-induced renal injury. Additionally, its mechanisms were also examined. Administration of kahweol attenuated renal dysfunction and histopathological damage together with inhibition of oxidative stress in cisplatin-injected mice. Increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and decreased expression of manganese superoxide dismutase and catalase after cisplatin treatment were significantly reversed by kahweol. Moreover, kahweol inhibited cisplatin-induced apoptosis and necroptosis in the kidneys. Finally, kahweol reduced inflammatory cytokine production and immune cell accumulation together with suppression of nuclear factor kappa-B pathway and downregulation of vascular adhesion molecules. Together, these results suggest that kahweol ameliorates cisplatin-induced renal injury via its pleiotropic effects and might be a potential preventive option against cisplatin-induced nephrotoxicity.

scholarly journals Preservation of renal endothelial integrity and reduction of renal edema by aprotinin does not preserve renal perfusion and function following experimental cardiopulmonary bypass

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Nicole A. M. Dekker ◽  
Anoek L. I. van Leeuwen ◽  
Matijs van Meurs ◽  
Jill Moser ◽  
Jeannette E. Pankras ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Renal Injury ◽  
Weight Ratio ◽  
Kidney Injury ◽  
Dry Weight ◽  
Renal Perfusion ◽  
Plasma Creatinine ◽  
Microcirculatory Perfusion ◽  
Neutrophil Influx ◽  
Endothelial Integrity

Abstract Background Acute kidney injury is a severe complication following cardiopulmonary bypass (CPB) and is associated with capillary leakage and microcirculatory perfusion disturbances. CPB-induced thrombin release results in capillary hyperpermeability via activation of protease-activated receptor 1 (PAR1). We investigated whether aprotinin, which is thought to prevent thrombin from activating PAR1, preserves renal endothelial structure, reduces renal edema and preserves renal perfusion and reduces renal injury following CPB. Methods Rats were subjected to CPB after treatment with 33.000 KIU/kg aprotinin (n = 15) or PBS (n = 15) as control. A secondary dose of 33.000 KIU/kg aprotinin was given 60 min after initiation of CPB. Cremaster and renal microcirculatory perfusion were assessed using intravital microscopy and contrast echography before CPB and 10 and 60 min after weaning from CPB. Renal edema was determined by wet/dry weight ratio and renal endothelial structure by electron microscopy. Renal PAR1 gene and protein expression and markers of renal injury were determined. Results CPB reduced cremaster microcirculatory perfusion by 2.5-fold (15 (10–16) to 6 (2–10) perfused microvessels, p < 0.0001) and renal perfusion by 1.6-fold (202 (67–599) to 129 (31–292) au/sec, p = 0.03) in control animals. Both did not restore 60 min post-CPB. This was paralleled by increased plasma creatinine (p < 0.01), neutrophil gelatinase-associated lipocalin (NGAL; p = 0.003) and kidney injury molecule-1 (KIM-1; p < 0.01). Aprotinin treatment preserved cremaster microcirculatory perfusion following CPB (12 (7–15) vs. 6 (2–10) perfused microvessels, p = 0.002), but not renal perfusion (96 (35–313) vs. 129 (31–292) au/s, p > 0.9) compared to untreated rats. Aprotinin treatment reduced endothelial gap formation (0.5 ± 0.5 vs. 3.1 ± 1.4 gaps, p < 0.0001), kidney wet/dry weight ratio (4.6 ± 0.2 vs. 4.4 ± 0.2, p = 0.046), and fluid requirements (3.9 ± 3.3 vs. 7.5 ± 3.0 ml, p = 0.006) compared to untreated rats. In addition, aprotinin treatment reduced tubulointerstitial neutrophil influx by 1.7-fold compared to untreated rats (30.7 ± 22.1 vs. 53.2 ± 17.2 neutrophil influx/section, p = 0.009). No differences were observed in renal PAR1 expression and plasma creatinine, NGAL or KIM-1 between groups. Conclusions Aprotinin did not improve renal perfusion nor reduce renal injury during the first hour following experimental CPB despite preservation of renal endothelial integrity and reduction of renal edema.

scholarly journals 4-Hydroxychalcone Attenuates Hyperaldosteronism, Inflammation, and Renal Injury in Cryptochrome-Null Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Qi Qu ◽  
Bingguang Dai ◽  
Bo Yang ◽  
Xuelian Li ◽  
Yimin Liu ◽  
...  
Keyword(s):  
Resistant Hypertension ◽  
Renal Injury ◽  
Systolic Pressure ◽  
Kidney Injury ◽  
High Plasma ◽  
Salt Treatment ◽  
Injury Treatment ◽  
The Impact ◽  
Preventive Effects ◽  
Light Chain Enhancer

In the present study, we aimed to investigate the preventive effects of 4-hydroxychalcone (4HCH) on resistant hypertension. We used cryptochrome-null mice, which characteristically show high plasma aldosterone levels, inflammation, and renal injury. The cryptochrome-null mice received high-salt treatment and were treated orally with 4HCH 10 mg/kg, 4HCH 20 mg/kg, and 4HCH 40 mg/kg, respectively. The salt administration in cryptochrome-null mice is able to induce an increase in systolic pressure which is associated with hyperaldosteronism, inflammation, and kidney injury. Treatment with 40 mg/kg 4HCH reduced systolic hypertension, serum IL-1β, and TNF-αlevels and suppressed the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and renal injury. The impact of 4HCH on the hyperaldosteronism, inflammation, and kidney injury provides new insights for future development of therapeutic strategies in resistant hypertension.

scholarly journals Autophagy Function and Regulation in Kidney Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 100 ◽  
Author(s):  
Gur P. Kaushal ◽  
Kiran Chandrashekar ◽  
Luis A. Juncos ◽  
Sudhir V. Shah
Keyword(s):  
Cell Death ◽  
Renal Injury ◽  
Mammalian Target Of Rapamycin ◽  
Kidney Injury ◽  
Therapeutic Approaches ◽  
Regulated Necrosis ◽  
Atg Genes ◽  
Cellular Components ◽  
The Impact

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

Protective effect of febuxostat in sepsis-induced liver and kidney injuries after cecal ligation and puncture with the impact of xanthine oxidase, interleukin 1β, and c-Jun N-terminal kinases

2020 ◽  
Vol 39 (7) ◽  
pp. 906-919 ◽  
Author(s):  
YF Ibrahim ◽  
RR Fadl ◽  
SAE Ibrahim ◽  
MF Gayyed ◽  
AMA Bayoumi ◽  
...  
Keyword(s):  
Protective Effect ◽  
Xanthine Oxidase ◽  
Tissue Injury ◽  
Cecal Ligation ◽  
Elevated Serum ◽  
Albino Rats ◽  
Cecal Ligation And Puncture ◽  
Necrosis Factor Alpha ◽  
Liver And Kidney ◽  
The Impact

Sepsis is one of the most common causes of death among hospitalized patients. Activity of xanthine oxidase (XO), a reactive oxygen species-producing enzyme, is known to be elevated in septic patients. Our aim was to investigate the possible protective role of XO inhibitor, febuxostat (FEB), in a rat model of sepsis-induced liver and kidney injures. Adult male albino rats were divided into four groups ( n = 12 each): sham control, sham + FEB, cecal ligation and puncture (CLP), and CLP + FEB groups. FEB (10 mg/kg per os (p.o.)) was given once daily for 2 days and 30 min prior to laparotomy with CLP. CLP was associated with a high mortality rate accompanied by significant liver and kidney injuries indicated by elevated serum alanine aminotransferase, aspartate aminotransferase, urea, and creatinine levels and confirmed by histopathological tissue injury. Moreover, there was an increase in neutrophil gelatinase-associated lipocalin, uric acid, malondialdehyde, and nitric oxide levels and with decreased superoxide dismutase activity and total antioxidant capacity. In addition, CLP caused increased expression of the inflammatory markers tumor necrosis factor alpha, interleukin 1beta protein levels, and nuclear factor kappa B immunoexpression. Finally, CLP operated rats exhibited an upregulation in the apoptotic mediators, caspase 3, and P-C-Jun N-terminal kinases (JNK) proteins. FEB treatment of CLP rats caused a significant improvement and normalization in all measured parameters. Moreover, FEB amerliorates degenerative histopathological changes and improves the overall survival rate. In conclusion, FEB exhibited a protective effect in sepsis-induced liver and kidney injuries most probably through its anti-inflammatory, antioxidant, and antiapoptotic properties and attenuating JNK signaling pathway secondary to its XO enzyme inhibitory activity.

scholarly journals Macrophage-Derived Iron-Bound Lipocalin-2 Correlates with Renal Recovery Markers Following Sepsis-Induced Kidney Damage

2020 ◽  
Vol 21 (20) ◽  
pp. 7527 ◽  
Author(s):  
Christina Mertens ◽  
Laura Kuchler ◽  
Anna Sola ◽  
Roser Guiteras ◽  
Stephan Grein ◽  
...  
Keyword(s):  
Renal Injury ◽  
Cultured Cells ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Renal Recovery ◽  
Iron Loading ◽  
Lipocalin 2 ◽  
Patient Death ◽  
Short Term ◽  
Cellular Source

During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls’ staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury.

scholarly journals Targeting acute kidney injury in COVID-19

2020 ◽  
Vol 35 (10) ◽  
pp. 1652-1662 ◽  
Author(s):  
John A Kellum ◽  
J W Olivier van Till ◽  
George Mulligan
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Endothelial Damage ◽  
Acid Oxidation ◽  
Acid Base ◽  
The Impact ◽  
Pathophysiologic Mechanisms

Abstract As of 15 August 2020, Coronavirus disease 2019 (COVID-19) has been reported in &gt;21 million people world-wide and is responsible for more than 750,000 deaths. The occurrence of acute kidney injury (AKI) in patients hospitalized with COVID-19 has been reported to be as high as 43%. This is comparable to AKI in other forms of pneumonia requiring hospitalization, as well as in non-infectious conditions like cardiac surgery. The impact of AKI on COVID-19 outcomes is difficult to assess at present but, similar to other forms of sepsis, AKI is strongly associated with hospital mortality. Indeed, mortality is reported to be very low in COVID-19 patients without AKI. Given that AKI contributes to fluid and acid–base imbalances, compromises immune response and may impair resolution of inflammation, it seems likely that AKI contributes to mortality in these patients. The pathophysiologic mechanisms of AKI in COVID-19 are thought to be multifactorial including systemic immune and inflammatory responses induced by viral infection, systemic tissue hypoxia, reduced renal perfusion, endothelial damage and direct epithelial infection with Severe Acute Respiratory Syndrome Coronavirus 2. Mitochondria play a central role in the metabolic deregulation in the adaptive response to the systemic inflammation and are also found to be vital in response to both direct viral damage and tissue reperfusion. These stress conditions are associated with increased glycolysis and reduced fatty acid oxidation. Thus, there is a strong rationale to target AKI for therapy in COVID-19. Furthermore, many approaches that have been developed for other etiologies of AKI such as sepsis, inflammation and ischemia–reperfusion, have relevance in the treatment of COVID-19 AKI and could be rapidly pivoted to this new disease.

scholarly journals Melatonin Alleviates Renal Injury in Mouse Model of Sepsis

2021 ◽  
Vol 12 ◽  
Author(s):  
Liyang Chen ◽  
Zhijian Han ◽  
Zhiguang Shi ◽  
Chao Liu ◽  
Qiulun Lu
Keyword(s):  
Renal Injury ◽  
Oxidant Stress ◽  
Mrna Level ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Role ◽  
Cecal Ligation Puncture ◽  
Species Production

Melatonin (N-acetyl-5-methoxytryptamine; MLT) has been shown to have a renal-protective effect against kidney injury. However, the mechanisms underlying the protective role of MLT in sepsis-induced renal injury are yet to be revealed. In this study, MLT alleviated renal dysfunction with the increase of BUN (blood urea nitrogen) and SCR (serum creatinine) and reduction of fibrosis in the CLP (cecal ligation puncture) model. RNA-seq analysis showed that MLT repressed the oxidant stress in response to kidney injury. Our in vitro study showed that MLT suppresses LPS-induced accumulation of ROS (reactive oxygen species) production via SOD2 downregulation and Nox4 upregulation in HK-2 cells. Furthermore, we found that MLT alleviated the inflammatory response, with the mRNA-level reduction of Il-1α, Il-1β, Mcp-1, and Tgf-β1. Taken together, in evaluating the therapeutic effect of MLT on sepsis-induced acute kidney injury, the results showed that MLT alleviated renal damage by regulating the production of ROS.

scholarly journals Antioxidant and anti-inflammatory effect of ligustilide on sepsis-induced acute kidney injury via TLR4/NF-κB and Nrf2/HO-1 signaling

2021 ◽  
Vol 20 (1) ◽  
pp. 83-87
Author(s):  
Xiumin Yang ◽  
Chencai Qiao ◽  
Chao Zheng ◽  
Qingjun Deng
Keyword(s):  
Acute Kidney Injury ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Serum Levels ◽  
Heme Oxygenase 1 ◽  
Protein Levels ◽  
Anti Inflammatory ◽  
Commercial Kits

Purpose: To investigate the protective effect of ligustilide on sepsis-induced acute kidney injury (AKI) and the signaling pathways involved.Methods: Sepsis-induced AKI was established by cecal ligation and puncture (CLP) in mice. Histopathological renal damage was examined using hematoxylin and eosin (H & E) staining while creatinine and cytokines were measured using commercial kits. Protein levels were determined by Western blotting.Results: Vacuoles, dilations, degeneration, and necrosis were observed in CLP mouse kidneys, but these alterations were countered by 20 mg/kg of ligustilide. Serum creatinine, blood urea nitrogen (BUN), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were significantly increased in CLP mice compared with control. Furthermore, the serum levels of these indicators in serum were lowered by ligustilide (p < 0.01). The expression levels of Toll-like receptor 4 (TLR4) TLR4 and phosphorylated nuclear factor (NF)-κB in CLP mice were also downregulated by ligustilide. Malondialdehyde (MDA) and myeloperoxidase (MPO) levels increased in CLP mice, but were attenuated by ligustilide (p < 0.01). Superoxide dismutase (SOD) and glutathione (GSH) levels decreased in CLP mice but were increased by ligustilide (p < 0.01). Increased expression of Nrf2 and heme oxygenase-1 (HO-1) were observed in CLP mice, and were further enhancced by ligustilide.Conclusion: Ligustilide exerts antioxidant and anti-inflammatory effects on sepsis-induced AKI via TLR4/NF-κB and Nrf2/HO-1 signaling pathways. Keywords: Ligustilide, Sepsis, Acute kidney injury, TLR4/NF-κB signaling pathway, Nrf2/HO-1 signaling pathway

scholarly journals Immunomodulatory Effect of Vitamin C on Proinflammatory Cytokines Production in Ossimi Lambs (Ovis aries) with Pneumonic Pasteurellosis

Animals ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 3374
Author(s):  
Mohamed Abdo Rizk ◽  
Shimaa Abd El-Salam El-Sayed ◽  
Doaa Salman ◽  
Basma H. Marghani ◽  
Hossam Elshahat Gadalla ◽  
...  
Keyword(s):  
Vitamin C ◽  
Inflammatory Cytokines ◽  
Interleukin 1 ◽  
Serum Levels ◽  
Ovis Aries ◽  
Necrosis Factor Alpha ◽  
Pneumonic Pasteurellosis ◽  
Tnf Α ◽  
The Impact ◽  
Pro Inflammatory Cytokines

In this study, we have investigated the impact of vitamin C on the production of pro-inflammatory cytokines (interleukin 1 β (IL-1 β), interleukin 6 (IL-6), interleukin 12p40 (IL-12p40), interferon gamma (IFNγ), and tumor necrosis factor alpha (TNF-α)) in lambs naturally infected by pneumonic pasteurellosis. Of 37 lambs, 18 lambs were identified to have pneumonic pasteurellosis and randomly allocated into two equal groups. Single subcutaneous dose of tulathromycine alone (2.5 mg kg−1) or tulathromycine combined with vitamin C (3 gm kg−1) were administrated to the diseased lambs. The serum levels of IL-1β, IL-6, IFN-γ, and TNF-α were returned to the normal levels in pneumonic lambs treated with the combination therapy. The obtained results indicate the selective influences of vitamin C on pro-inflammatory cytokines production in sera of lambs with pneumonic pasteurellosis and highlights the value of vitamin C as a potential anti-inflammatory drug and ideal immunomodulatory agent.

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