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.

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 Letrozole-Induced Polycystic Ovary Syndrome Attenuates Cystathionine-β Synthase Gene Expression in the Ovaries of Female Sprague Dawley Rats

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1244-1244
Author(s):  
Amanda Bries ◽  
Joe Webb ◽  
Brooke Vogel ◽  
Claudia Carrillo ◽  
Aileen Keating ◽  
...  
Keyword(s):  
Gene Expression ◽  
Polycystic Ovary Syndrome ◽  
Mrna Expression ◽  
Polycystic Ovary ◽  
Elevated Serum ◽  
Reproductive Age ◽  
Sprague Dawley ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Sd Rats

Abstract Objectives Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10% of reproductive age women and leads to hyperandrogenism, abnormal menstrual cycles, and polycystic ovaries. Moreover, PCOS has been associated with elevated serum homocysteine; however, the characterization of one-carbon metabolism (OCM) in PCOS remains incomplete. The aim of our research was to examine OCM in a genetic and chemically-induced rodent model of PCOS: 1) viable yellow Agouti (Avy) mice; and 2) letrozole (Let)-induced Sprague Dawley (SD) rats. Methods Five wk old female Avy mice (N = 18), their lean controls (N = 18), and SD rats (N = 36) were acclimated for one wk. Following acclimation, the animals were placed on a modified standard AIN93G diet (energy, %: 50.4, carbohydrate; 17.3, protein; and 32.3, fat). Rats were randomly assigned to Let (1 g/kg BW) treatment or vehicle (carboxymethylcellulose) control that was administered via a subcutaneously implanted slow-release pellet every 30-d. For both models, 12 animals were randomly assigned to be euthanized during proestrus at one of the following ages: 8, 16 or 24 wk. Bodyweight and estrous cycles were measured daily. Ovaries were collected to assess gene expression of OCM. These data were analyzed using linear mixed models to determine the main effects of age and treatment at a significance level of P < 0.05. Results Letrozole significantly reduced the occurrence of proestrus and estrus stages (P = 0.0001 and P = 0.006, respectively). Additionally, Let-induced rats had increased BW compared to control rats, across all age groups (P < 0.0001). In contrast, Avy mice weighed less than their controls by 24 wk of age (P < 0.0001). Cystathionine-β synthase (CBS) mRNA expression was downregulated in the Let-induced vs. control rats at 16 (59%; P < 0.05) and 24 (77%; P < 0.01) wk of age. As expected, Cyp19A1, aromatase mRNA was downregulated in the Let-induced rats (P = 0.02). Interestingly, betaine-homocysteine s-methyltransferase (BHMT) mRNA increased as a function of age in Let-induced rats (P = 0.03). Conclusions These data demonstrate that Letrozole-induced PCOS temporally decreases ovarian CBS mRNA expression; whereas, BHMT mRNA is upregulated as a function of age. Funding Sources This work was supported by the National Institute of Child Health and Human Development.

scholarly journals Determinants of Monocyte Apoptosis in Cardiorenal Syndrome Type 1

2018 ◽  
Vol 8 (3) ◽  
pp. 208-216 ◽  
Author(s):  
Andrea Breglia ◽  
Grazia Maria Virzì ◽  
Silvia Pastori ◽  
Alessandra Brocca ◽  
Massimo de Cal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Caspase 3 ◽  
Kidney Injury ◽  
Annexin V ◽  
Cardiorenal Syndrome ◽  
Pathophysiological Mechanism ◽  
Syndrome Type ◽  
Caspase 9 ◽  
Apoptotic Pathway

Background: Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Its pathophysiology is complex and not completely understood. In this study, we examined the role of apoptosis and the caspase pathways involved. Material and Methods: We enrolled 40 acute heart failure (AHF) patients, 11 of whom developed AKI characterizing CRS type 1. We exposed the human cell line U937 to plasma from the CRS type 1 and AHF groups and then we evaluated apoptotic activity by annexin-V evaluation, determination of caspase-3, -8 and -9 levels, and BAX, BAD, and FAS gene expression. Results: We observed significant upregulation of apoptosis in monocytes exposed to CRS type 1 plasma compared to AHF, with increased levels of caspase-3 (p < 0.01), caspase-9 (p < 0.01), and caspase-8 (p < 0.03) showing activation of both intrinsic and extrinsic pathways. Furthermore, monocytes exposed to CRS type 1 plasma had increased gene expression of BAX and BAD (intrinsic pathways) (p = 0.010 for both). Furthermore, strong significant correlations between the caspase-9 levels and BAD and BAX gene expression were observed (Spearman ρ = – 0.76, p = 0.011, and ρ = – 0.72, p = 0.011). Conclusion: CRS type 1 induces dual apoptotic pathway activation in monocytes; the two pathways converged on caspase-3. Many factors may induce activation of both intrinsic and extrinsic apoptotic pathways in CRS type 1 patients, such as upregulation of proinflammatory cytokines and hypoxia/ischemia. Further investigations are necessary to corroborate the present findings, and to better understand the pathophysiological mechanism and consequent therapeutic and prognostic implications for CRS type 1.

A Design Based Materials Study for a Wearable Muscle Stretching Device Aimed at Patients With Spasticity

2007 ◽  
Author(s):  
Michael Bailey-Van Kuren ◽  
Carter Hamilton ◽  
Eduardo Rivera
Keyword(s):  
Composite Structure ◽  
Treatment Options ◽  
Current Treatment ◽  
Sensor System ◽  
Wearable Sensor ◽  
Thin Film Sensors ◽  
Muscle Stretching ◽  
Serial Casting ◽  
Muscle Groups ◽  
And Control

The efficacy of robotic systems in rehabilitation is well established. Many of these systems are fixed equipment that requires the user to visit a facility for treatment. Furthermore, current treatment options for pediatric patients with spastic dyplagia include manual stretching of the muscle groups and serial casting in conjunction with Botox injections. The goal of this work is to develop a dynamic orthotic to stretch the muscles of the lower calf. A subsystem of this project is the development of wearable sensor system to detect spasticity and control the system actuators. A system of thin film sensors embedded into a novel composite structure is proposed. In order to develop a dynamic orthotic to stretch the muscles of the lower calf, a subsystem of this project is the development of wearable sensor system embedded into a novel composite structure [1, 2, 3].

scholarly journals Rat pancreatectomy combined with isoprenaline or uninephrectomy as models of diabetic cardiomyopathy or nephropathy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Louise Thisted ◽  
Mette V. Østergaard ◽  
Annemarie A. Pedersen ◽  
Philip J. Pedersen ◽  
Ross T. Lindsay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Analysis ◽  
Diabetic Cardiomyopathy ◽  
Gene Expression Analysis ◽  
Kidney Injury ◽  
Left Ventricular ◽  
Disease Development ◽  
Sprague Dawley ◽  
Novel Treatments ◽  
Urine Albumin

Abstract Cardiovascular and renal complications are the predominant causes of morbidity and mortality amongst patients with diabetes. Development of novel treatments have been hampered by the lack of available animal models recapitulating the human disease. We hypothesized that experimental diabetes in rats combined with a cardiac or renal stressor, would mimic diabetic cardiomyopathy and nephropathy, respectively. Diabetes was surgically induced in male Sprague Dawley rats by 90% pancreatectomy (Px). Isoprenaline (Iso, 1 mg/kg, sc., 10 days) was administered 5 weeks after Px with the aim of inducing cardiomyopathy, and cardiac function and remodeling was assessed by echocardiography 10 weeks after surgery. Left ventricular (LV) fibrosis was quantified by Picro Sirius Red and gene expression analysis. Nephropathy was induced by Px combined with uninephrectomy (Px-UNx). Kidney function was assessed by measurement of glomerular filtration rate (GFR) and urine albumin excretion, and kidney injury was evaluated by histopathology and gene expression analysis. Px resulted in stable hyperglycemia, hypoinsulinemia, decreased C-peptide, and increased glycated hemoglobin (HbA1c) compared with sham-operated controls. Moreover, Px increased heart and LV weights and dimensions and caused a shift from α-myosin heavy chain (MHC) to β-MHC gene expression. Isoprenaline treatment, but not Px, decreased ejection fraction and induced LV fibrosis. There was no apparent interaction between Px and Iso treatment. The superimposition of Px and UNx increased GFR, indicating hyperfiltration. Compared with sham-operated controls, Px-UNx induced albuminuria and increased urine markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and podocalyxin, concomitant with upregulated renal gene expression of NGAL and kidney injury molecule 1 (KIM-1). Whereas Px and isoprenaline separately produced clinical endpoints related to diabetic cardiomyopathy, the combination of the two did not accentuate disease development. Conversely, Px in combination with UNx resulted in several clinical hallmarks of diabetic nephropathy indicative of early disease development.

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

Early Detection of Renal Dysfunction in β Thalassemia with Focus on Novel Biomarkers

2020 ◽  
Author(s):  
Mozhgan Hashemieh
Keyword(s):  
Renal Dysfunction ◽  
Early Recognition ◽  
Binding Protein ◽  
Kidney Injury ◽  
Thalassemia Major ◽  
Retinol Binding Protein ◽  
Fatty Acid Binding ◽  
Novel Biomarkers ◽  
Beta 2 Microglobulin ◽  
Kidney Injury Molecule 1

Improved survival among transfusion dependent thalassemia patients in recent years has led to the manifestation of morbidities such as renal dysfunction. Renal injury is still an underestimated complication in β thalassemia major patients. Chronic anemia, iron overload due to repeated transfusion, and specific iron chelators are the main factors in pathogenesis of renal dysfunction in β thalassemia. Early identification of this morbidity allows us to delay the progression of kidney damage and therefore reduce renal impairment. In recent decades , novel biomarkers for early recognition of renal dysfunction have been studied in thalassemic patients, such as cystatin C, beta 2 microglobulin , alpha 1 microglobulin, N-acetyl beta-D-glucosaminidase (NAG), neutrophil gelatinase associated lipocaline (NGAL) , kidney injury molecule 1 (KIM-1) , liver type fatty acid binding protein (L-FABP), and retinol binding protein (RBP). In this review, renal aspects of thalassemia with focus on novel biomarkers were discussed.

scholarly journals The Pharmacodynamic-Toxicodynamic Relationship of AUC and CMAX in Vancomycin Induced Kidney Injury in an Animal Model

2020 ◽  
pp. AAC.01945-20
Author(s):  
Sean N. Avedissian ◽  
Gwendolyn Pais ◽  
Jiajun Liu ◽  
J. Nicholas O’Donnell ◽  
Thomas P. Lodise ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Information Criterion ◽  
Compartment Model ◽  
Model Fit ◽  
Sprague Dawley ◽  
P Values ◽  
Exposure Response ◽  
Sprague Dawley Rats ◽  
Kidney Injury Molecule 1 ◽  
Relationship Of

Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received IV vancomycin doses of 300mg/kg/day and 400mg/kg/day, divided once, twice, thrice or 4xdaily (i.e., QD, BID, TID or QID) over 24-hours. Up to 8-samples were drawn during the 24-hour dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via LC-MS/MS. Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e. AUC0-24h, CMAX0-24h,) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed vs. predicted concentrations, R2=0.96). KIM-1 values were greater in QD and BID groups (P-values: QD vs TID:<0.002, QD vs QID:<0.004, BID vs TID:<0.002, and BID vs QID:<0.004). Exposure–response relationships were observed between KIM-1 vs CMAX0-24h and AUC0–24h (R2 =  0.7 and 0.68). Corrected Akaike’s information criterion showed CMAX0-24h as most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (-5.28 versus -1.95).While PK-TD indices are often inter-correlated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.

scholarly journals Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model

2019 ◽  
Vol 74 (8) ◽  
pp. 2326-2334 ◽  
Author(s):  
Sean N Avedissian ◽  
Gwendolyn M Pais ◽  
J Nicholas O’Donnell ◽  
Thomas P Lodise ◽  
Jiajun Liu ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Compartment Model ◽  
Urinary Biomarkers ◽  
Daily Injection ◽  
Sprague Dawley ◽  
Exposure Response ◽  
Sprague Dawley Rats ◽  
Two Compartment Model ◽  
Kidney Injury Molecule 1 ◽  
Maximal Rise

Abstract Objectives To identify the pharmacokinetic (PK) and toxicodynamic (TD) relationship for vancomycin-induced kidney injury. Methods Male Sprague–Dawley rats received intravenous (iv) vancomycin. Doses ranging from 150 mg/kg/day to 400 mg/kg/day were administered as a single or twice-daily injection over 24 h (total protocol duration). Controls received iv saline. Plasma was sampled with up to eight samples in 24 h per rat. Twenty-four hour urine was collected and assayed for kidney injury molecule 1 (KIM-1), osteopontin and clusterin. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 h (i.e. AUC0–24h, Cmax 0–24h and Cmin 0–24h) were calculated. PK/TD relationships were assessed with Spearman’s rank coefficient (rs) and the best-fit mathematical model. Results PK/TD data were generated from 45 vancomycin-treated and 5 control rats. A two-compartment model fit the data well (Bayesian: observed versus predicted R2 = 0.97). Exposure–response relationships were found between AUC0–24h versus KIM-1 and osteopontin (R2 = 0.61 and 0.66) and Cmax 0–24h versus KIM-1 and osteopontin (R2 = 0.50 and 0.56) using a four-parameter Hill fit. Conversely, Cmin 0–24h was less predictive of KIM-1 and osteopontin (R2 = 0.46 and 0.53). A vancomycin AUC0–24h of 482.2 corresponded to a 90% of maximal rise in KIM-1. Conclusions Vancomycin-induced kidney injury as defined by urinary biomarkers is driven by vancomycin AUC or Cmax rather than Cmin. Further, an identified PK/TD target AUC0–24h of 482.2 mg·h/L may have direct relevance to human outcomes.

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.

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