scholarly journals Synergistic antioxidant capacity of CsNPs and CurNPs against cytotoxicity, genotoxicity and pro-inflammatory mediators induced by hydroxyapatite nanoparticles in male rats

2019 ◽  
Vol 8 (6) ◽  
pp. 939-952 ◽  
Author(s):  
Israa F. Mosa ◽  
Mokhtar Youssef ◽  
Maher Kamel ◽  
Osama F. Mosa ◽  
Yasser Helmy
Keyword(s):  
Gene Expression ◽  
Biochemical Parameters ◽  
Chitosan Nanoparticles ◽  
Kidney Injury ◽  
Toxicity Assessment ◽  
Male Rats ◽  
Lipocalin 2 ◽  
Hydroxyapatite Nanoparticles ◽  
Curcumin Nanoparticles ◽  
Kidney Injury Molecule 1

Abstract Due to their dynamic characteristics, hydroxyapatite nanoparticles (HAP-NPs) have been employed numerous times in nanomedicine and in tissue engineering, particularly as diagnostic and therapeutic agents. However, there are outstanding findings from various studies that question whether these NPs are safe when they are used in the human body. Therefore, a more in-depth toxicity assessment should be carried out to give a clear answer regarding the fate of these particles. Here we aim to investigate the possible cytotoxicity, genotoxicity and inflammation induced by HAP-NPs, as well as predict the synergistic antioxidative effect of chitosan nanoparticles (CsNPs) and curcumin nanoparticles (CurNPs) in mitigating this pronounced toxicity. The present study was conducted on eighty Wistar male rats, divided into eight equal groups. The results showed that, at the molecular level, HAP-NPs significantly induced gene expression of tumor suppressor protein p53, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and also Kidney Injury Molecule-1 (KIM-1) and Lipocalin-2 (LCN2). In addition, kidney biochemical parameters (total bilirubin, urea, uric acid and creatinine) increased, but albumin levels decreased in the group treated with HAP-NPs alone. Meanwhile, co-treatment with CsNPs and/or CurNPs with HAP-NPs showed an improvement in the activities of the kidney parameters and reduced inflammation. This study shows that the nephrotoxicity mechanism of HAP-NPs may involve various signaling pathways including alterations in biochemical parameters, gene expression of KIM-1 and LCN2 and disturbing the production of cytokines and p53. Furthermore, these insights showed that the combined effect of both CsNPs and CurNPs was more pronounced than the effect of each one on its own.

scholarly journals Chitosan and Curcumin Nanoformulations against Potential Cardiac Risks Associated with Hydroxyapatite Nanoparticles in Wistar Male Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Israa F. Mosa ◽  
Haitham H. Abd ◽  
Abdelsalam Abuzreda ◽  
Amenh B. Yousif ◽  
Nadhom Assaf
Keyword(s):  
Cardiac Tissue ◽  
Chitosan Nanoparticles ◽  
Mitochondrial Pathway ◽  
Serum Markers ◽  
Male Rats ◽  
Circulation System ◽  
Hydroxyapatite Nanoparticles ◽  
Necrosis Factor Alpha ◽  
Curcumin Nanoparticles ◽  
Blood Circulation System

Nanoparticle-induced cardiovascular diseases have attracted much attention. Upon entering the blood circulation system, these particles have the potency to induce cardiomyocytes, leading to cardiac failure or myocardial ischemia, and the molecular mechanism remains to be completely clarified. In this study, the cardiac toxicity of rats orally exposed to hydroxyapatite nanoparticles (HAPNPs) has been observed through an increase in myocardial infarction serum markers including CK-MB and alterations in routine blood factors, expression of apoptosis-related protein P53, and increased levels of serum inflammatory markers represented by the tumor necrosis factor alpha and Interleukin-6, as well as a decline in heart antioxidant enzymes and reduced glutathione level, while an induction in lipid peroxidation and nitric oxide has been observed, as well as notable histological and histochemical alterations in the heart of these animals. mRNA and protein expressions of vascular endothelial growth factor (VEGF-A), cyclooxygenase-2 (COX-2), and atrial natriuretic factor (ANF) were elevated in the myocardium. However, the coadministration of chitosan nanoparticles (CsNPs) and/or curcumin nanoparticles (CurNPs) successfully modulated these alterations and induced activation in antioxidant parameters. The present data suggest that HAPNPs-induced apoptosis via the mitochondrial pathway may play a crucial role in cardiac tissue damage and the early treatment with CsNPs and CurNPs may protect the heart from infarction induced by HAPNPs toxic effect.

Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition

2010 ◽  
Vol 298 (6) ◽  
pp. F1472-F1483 ◽  
Author(s):  
Gang Jee Ko ◽  
Dmitry N. Grigoryev ◽  
Douglas Linfert ◽  
Hye Ryoun Jang ◽  
Tonya Watkins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatitis A Virus ◽  
Ischemia Reperfusion Injury ◽  
Early Stage ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Transcriptional Analysis ◽  
Lipocalin 2 ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Kidney Injury Molecule 1

Acute kidney injury (AKI) is being increasingly shown to be a risk factor for chronic kidney disease (CKD), but little is known about the possible mechanistic links. We hypothesized that analysis of the genomic signature in the repair stage after AKI would reveal pathways that could link AKI and CKD. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6J mice. Mice were euthanized at 3, 10, and 28 days after ischemia-reperfusion injury (IRI). Total RNA was isolated from kidney and analyzed using an Illumina mouse array. Among 24,600 tested genes, 242, 146, and 46 genes were upregulated at days 3, 10, and 28 after IRI, and 85, 35, and 0 genes were downregulated, respectively. Gene ontology analysis showed that gene expression changes were primarily related to immune and inflammatory pathways both early and late after AKI. The most highly upregulated genes late after AKI were hepatitis A virus cellular receptor 1 ( Havcr1) and lipocalin 2 ( Lcn2), which code for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), respectively. This was unexpected since they are both primarily potential biomarkers of the early stage of AKI. Furthermore, increases observed in gene expression in amiloride binding protein 1, vascular cell adhesion molecule-1, and endothelin 1 could explain the salt-sensitive hypertension that can follow AKI. These data suggested that 1) persistent inflammation and immune responses late after AKI could contribute to the pathogenesis of CKD, 2) late upregulation of KIM-1 and NGAL could be a useful marker for sustained renal injury after AKI, and 3) hypertension-related gene changes could underlie mechanisms for persistent renal and vascular injury after AKI.

scholarly journals Attenuation of Circulating Trimethylamine N-Oxide Prevents the Progression of Cardiac and Renal Dysfunction in a Rat Model of Chronic Cardiorenal Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Deling Zou ◽  
Yanyu Li ◽  
Guangping Sun
Keyword(s):  
Gene Expression ◽  
Renal Dysfunction ◽  
Treatment Options ◽  
Elevated Serum ◽  
Kidney Injury ◽  
Cardiorenal Syndrome ◽  
Current Treatment ◽  
Sprague Dawley ◽  
Kidney Injury Molecule 1 ◽  
And Control

Chronic heart failure (HF) frequently causes progressive decline in kidney function, known as cardiorenal syndrome-2 (CRS2). Current treatment options for CRS2 remain unacceptably limited. Trimethylamine-N-oxide (TMAO), a metabolite of gut microbiota, has recently been implicated in the pathogenesis of both HF and chronic kidney disease. Here we examined whether circulating TMAO is elevated in CRS2 and if so, whether attenuation of circulating TMAO would ameliorate the progression of CRS2. Sprague-Dawley rats underwent surgery for myocardial infarction (MI) or sham (week 0) followed by subtotal (5/6) nephrectomy (STNx) or sham at week 4 to induce CRS2 or control. At week 6, MI + STNx rats and control rats received vehicle or 1.0% 3,3-Dimethyl-1-butanol (DMB, a TMAO inhibitor) treatment for 8 weeks. Compared with control rats, MI + STNx rats exhibited elevated serum TMAO at week 6, which was increased further at week 14 but was attenuated by DMB treatment. MI + STNx rats showed cardiac dysfunction as assessed by echocardiography and renal dysfunction as evidenced by increased serum creatinine and urinary kidney injury molecule-1 and decreased creatinine clearance at week 6. The cardiac and renal dysfunction in MI + STNx rats was exacerbated at week 14 but was prevented by DMB treatment. Molecular and histological studies revealed myocyte hypertrophy and increases in interstitial myocardial fibrosis and gene expression of pro-hypertrophic and pro-fibrotic markers in both heart and kidney at week 14, which were accompanied by elevated gene expression of proinflammatory cytokines. The changes in molecular and histological parameters observed in MI + STNx rats were significantly reduced by DMB treatment. These findings suggest that rats with CRS2 have elevated circulating TMAO, which is associated with the exacerbation of cardiac and renal dysfunction. Attenuation of circulating TMAO can ameliorate cardiac and renal injury and prevents the progression of CRS2.

Gene expression approach to evaluate kidney injury molecule-1 (KIM-1) as a predictive marker for renal toxicity

2010 ◽  
Vol 196 ◽  
pp. S245
Author(s):  
A. Chiusolo ◽  
R. Defazio ◽  
P. Cristofori ◽  
M. Mongillo ◽  
E. Zanetto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Toxicity ◽  
Kidney Injury ◽  
Predictive Marker ◽  
Kidney Injury Molecule 1

Effects of prophylactic administration of glutamine on CD4+ T cell polarisation and kidney injury in mice with polymicrobial sepsis

2019 ◽  
Vol 122 (6) ◽  
pp. 657-665 ◽  
Author(s):  
Yu-Chen Hou ◽  
Jin-Ming Wu ◽  
Kuen-Yuan Chen ◽  
Po-Da Chen ◽  
Cing-Syuan Lei ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Late Phase ◽  
Kidney Injury ◽  
Polymicrobial Sepsis ◽  
Control Group ◽  
T Cell Apoptosis ◽  
Inflammatory Protein ◽  
Kidney Injury Molecule 1

AbstractThe present study investigated the effects of glutamine (GLN) pretreatment on CD4+ T cell polarisation and remote kidney injury in mice with gut-derived polymicrobial sepsis. Mice were randomly assigned to three groups: normal control fed with American Institute of Nutrition (AIN)-93G diet and two sepsis groups provided with either AIN-93G-based diet or identical components, except part of casein was replaced by GLN. Mice were given their respective diets for 2 weeks. Then, mice in the sepsis groups were performed with caecal ligation and puncture and were killed 72 h after the surgery. Blood, spleens and kidneys were collected for further examination. The results showed that sepsis resulted in decreased circulating and splenic total T lymphocyte and CD4+ T cell percentages, whereas IL-4-, and forkhead box p3 (Foxp3)-expressing CD4+ T cells percentages were up-regulated. Compared with the sepsis control group, pretreatment with GLN maintained blood T and CD4+ T cells and reduced percentages of IL-4- and Foxp3-expressing CD4+ T cells. Also, a more pronounced activation and increased anti-apoptotic Bcl-2 gene expression of splenic CD4+ T cells were observed. Concomitant with the decreased plasma IL-6, keratinocyte-derived chemokine (KC) levels, the gene expression of KC, macrophage inflammatory protein-2 and renal injury biomarker kidney injury molecule-1 (Kim-1) were down-regulated when GLN was administered. These findings suggest that antecedent of GLN administration elicit a more balanced blood T helper cell polarisation, sustained T cell populations, prevented splenic CD4+ T cell apoptosis and attenuated kidney injury at late phase of polymicrobial sepsis. GLN may have benefits in subjects at risk of abdominal infection.

Transcriptome-based identification of pro- and antioxidative gene expression in kidney cortex of nitric oxide-depleted rats

2007 ◽  
Vol 28 (2) ◽  
pp. 158-167 ◽  
Author(s):  
Sebastiaan Wesseling ◽  
Jaap A. Joles ◽  
Harry van Goor ◽  
Hans A. Bluyssen ◽  
Patrick Kemmeren ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Transcriptional Response ◽  
Kidney Injury ◽  
Kidney Cortex ◽  
Heme Oxygenase 1 ◽  
Sprague Dawley ◽  
Expression Of Genes ◽  
Proinflammatory Gene ◽  
Kidney Injury Molecule 1

Nitric oxide (NO) depletion in rats induces severe endothelial dysfunction within 4 days. Subsequently, hypertension and renal injury develop, which are ameliorated by α-tocopherol (VitE) cotreatment. The hypothesis of the present study was that NO synthase (NOS) inhibition induces a renal cortical antioxidative transcriptional response and invokes pro-oxidative and proinflammatory gene expression due to elimination of dampening effects of NO and enhanced oxidative stress. Male Sprague-Dawley rats received NOS inhibitor Nω-nitro-l-arginine (l-NNA, 500 mg/l water) for 4 (4d-LNNA), 21 (21d-LNNA), or 21 days with VitE in chow (0.7 g/kg body wt/day). Renal cortical RNA was applied to oligonucleotide rat arrays. In 4d-LNNA, 21d-LNNA, and 21d-LNNA+VitE, 120, 320, and 184 genes were differentially expressed, respectively. Genes related to glutathione and bilirubin synthesis were suppressed during 4d and 21d-LNNA and not corrected by VitE. Proteinuria, tubulointerstitial macrophages, and heme-oxygenase-1 (HO-1) expression were strongly correlated. Remarkably, pro-oxidative genes were not induced. Inflammation- and injury-related genes, including kidney injury molecule-1 and osteopontin, were unchanged at day 4, induced at 21d, and partly corrected by VitE. Superimposing HO-1 inhibition on NOS inhibition had no impact on the development of hypertension. To summarize, renal expression of genes involved in synthesis of the antioxidants glutathione and bilirubin seemed directly NO dependent, but there were no direct effects of NO depletion on pro-oxidant systems. This indicates that renal transcriptional regulation of two defense systems, glutathione and bilirubin syntheses, seems to depend upon adequate NO synthesis. Interaction between NO synthesis and heme degradation pathways for blood pressure regulation was not found.

scholarly journals Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

2013 ◽  
Vol 304 (11) ◽  
pp. R951-R958 ◽  
Author(s):  
Andrea Soljancic ◽  
Arnaldo Lopez Ruiz ◽  
Kiran Chandrashekar ◽  
Rodrigo Maranon ◽  
Ruisheng Liu ◽  
...  
Keyword(s):  
Renal Dysfunction ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Serum Testosterone ◽  
Protective Role ◽  
Male Rats ◽  
Plasma Creatinine ◽  
Acute Ischemia ◽  
Kidney Injury Molecule 1

Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease, in general. In the present study, we tested the hypothesis that I/R of the kidney reduces serum testosterone, and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 h after reperfusion that remained at 24 h. Acute infusion of testosterone 3 h after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 h, prevented the reduction in outer medullary blood flow, and attenuated the increase in intrarenal TNF-α and the decrease in intrarenal VEGF at 48 h. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 h than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney, whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol.

scholarly journals Salutary Effects of Cepharanthine against Skeletal Muscle and Kidney Injuries following Limb Ischemia/Reperfusion

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Ming-Chang Kao ◽  
Chih-Yang Chung ◽  
Ya-Ying Chang ◽  
Chih-Kung Lin ◽  
Joen-Rong Sheu ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Limb Ischemia ◽  
Male Rats ◽  
Prostaglandin E ◽  
Muscle Creatine Kinase ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Anti Inflammatory ◽  
Kidney Injury Molecule 1

Limb ischemia/reperfusion (I/R) causes oxidation and inflammation and subsequently induces muscle and kidney injuries. Cepharanthine, a natural plant alkaloid, possesses anti-inflammatory and antioxidative properties. We elucidated the salutary effects of cepharanthine against muscle and kidney injuries following limb I/R. Adult male rats were randomized to receive I/R or I/R plus cepharanthine. I/R was achieved by applying tourniquet high around each thigh for 3 hours followed by reperfusion for 24 hours. Cepharanthine (10 mg/kg, intraperitoneal) was injected immediately before reperfusion. After euthanization, degrees of tissue injury, inflammation, and oxidation were examined. Our data revealed that the I/R group had significant increases in injury biomarker concentrations of muscle (creatine kinase and lactate dehydrogenase) and kidney (creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1). Histological assays revealed moderate muscle and kidney injury characteristics in the I/R group. The I/R group also had significant increases in concentrations of inflammatory molecules (interleukin-6, macrophage inflammatory protein-2, and prostaglandin E2) and reactive nitrogen species (nitric oxide) as well as lipid peroxidation (malondialdehyde). Of note, these effects of limb I/R could be mitigated by cepharanthine. These data confirmed that cepharanthine attenuated muscle and kidney injuries induced by limb I/R. The mechanisms may involve its anti-inflammatory and antioxidative capacities.

scholarly journals Drug-induced Obstructive and Retrograde Nephropathy Associated with α2u-globulin in Male Rats

2018 ◽  
Vol 47 (2) ◽  
pp. 138-149
Author(s):  
Björn Jacobsen ◽  
Christian Freichel ◽  
Anne Eichinger-Chapelon ◽  
Andreas Brink ◽  
Jean-Christophe Hoflack ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Female Rats ◽  
Male Rats ◽  
Mechanistic Study ◽  
Obstructive Nephropathy ◽  
Dependent Manner ◽  
Intact Male ◽  
Drug Induced ◽  
Specific Syndrome ◽  
Kidney Injury Molecule 1

The chemically induced accumulation of α2u-globulin protein in male rats causes specific renal lesions and subsequent nephropathy. Herein, we report additional parallel findings in the kidney of male rats consistent with obstructive and retrograde nephropathy. Kidney and urinary bladder samples were evaluated from Wistar rats treated with RG7129 for 2 week and 8 week and from an 8-week mechanistic study using females, intact and castrated males. Histopathological findings were present in intact males in all studies, including hyaline droplet accumulation and granular casts consistent with α2u-globulin nephropathy. In addition, tubular degeneration and regeneration, tubular changes extending from papilla to cortex, tubular dilation, and interstitial and luminal inflammation were observed consistent with retrograde and obstructive nephropathy. Renal and urinary lesions and their severity increased in a time- and dose-dependent manner. Urinalysis findings, including increases in leukocytes, protein, and in kidney biomarkers, kidney injury molecule 1 and clusterin, were present only in intact males. No treatment-related changes were observed in female rats or in castrated males. These results indicate that RG7129 induces α2u-globulin nephropathy, associated with retrograde and obstructive nephropathy secondary to precipitation in intact male rats only, constituting a species- and sex-specific syndrome that is not expected to occur in humans or other species.

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