Abstract 229: Increased Ace Gene Dosage Reduces Ace2 Activity in Diabetic Mice Kidney: Involvement of Ace/ace2 Balance on the Development of Diabetic Nephropathy

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Nadia S Bertoncello ◽  
Roseli P Moreira ◽  
Rodrigo Yokota ◽  
Rodolfo M Rosa ◽  
Danielle Y Arita ◽  
...  
Keyword(s):  
Body Weight ◽  
Diabetic Nephropathy ◽  
Gene Dosage ◽  
Weight Ratio ◽  
Gene Copy ◽  
Diabetic Mice ◽  
Body Weight Ratio ◽  
Ace Gene ◽  
Kidney Involvement ◽  
Ace Activity

The mechanisms underlying the link between high constitutive levels of ACE and diabetic nephropathy has not been completely understood, but an imbalance between angiotensin I (ACE) and II (ACE2) converting enzymes homeostasis has been described in diabetic kidney disease. The aim of this study was to evaluate ACE/ACE2 homeostasis in kidney from diabetic mice presenting increased dosage of ACE gene. Male mice (3 months old) genetically engineered to harbor one or three copies of the ACE gene were made diabetic (streptozotocin - STZ, 50 mg/Kg) and randomly assigned into: 1-copy control (1CC), 1-copy diabetic (1CD), 3-copy control (3CC) and 3-copy diabetic. At the end of experimental period body weight was evaluated and kidney was excised. Kidney-to-body weight ratio and ACE and ACE 2 activities were determined using specific substrates (ZPhe-HL and 7-Mca-APK(Dnp), respectively) (Two way ANOVA + Tukey test; P<0.05). Diabetes increased blood glucose (1CD : 436 ± 25 vs. 1CC: 90 ± 2; 3CD: 556 ± 6 vs. 3CC: 112 ± 4 mg/dL) and kidney-to-body weight ratio (1CD: 7.5 ± 0.2 vs. 1CC: 5.8 ± 0.2; 3CD: 7.8 ± 0.1 vs. 3CC: 5.8 ± 0.1 mg/g) with no influence of ACE genotype. As expected, renal ACE activity was directly related to ACE gene copy number in control group (3CC: 9.4 ± 2.11 vs. 1CC:5.6 ± 0.9 mU/mg protein). Renal ACE activity was decreased in diabetic groups (1CD: 3.6 ± 0.2 vs. 1CC: 5.6 ± 0.9; 3CD: 2.3 ± 0.4 vs. 3CC: 9.4 ± 2.1 mU/mg protein) with no influence of ACE genotype. Under physiological condition, renal ACE2 activity remained unchanged regardless of the ACE genotype (1CC: 1.9 ± 0.2 = 3CC: 1.4 ± 0.1 μM/min/mg). However upon a pathological stimulus, renal ACE2 activity was efficiently increased only in 1CD group, but not in 3CD, as compared with the others (1CD: 5.1 ± 0.9 vs. 1CC: 1.9 ± 0.2 = 3CC: 1.4 ± 0.1 = 3CD: 2.2 ± 0.2 μM/min/mg). Taken together, our results show for the first time, that susceptibility for the development of diabetic nephropathy associated with increased ACE gene dosage may be, at least in part, caused by a decrease on renal ACE2 activity. This may result in increased local levels of angiotensin II and decreased angiotensin (1-7), leading to altered glomerular permeability and albuminuria, functional alterations presented by 3CD animals. Financial Support: FAPESP, CAPES, CNPq.

scholarly journals ADAMTS13/VWF Axis Potentially Contributes to Diabetic Nephropathy By Regulating PAI-1 Levels

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2240-2240
Author(s):  
Nirav Dhanesha ◽  
Anil K. Chauhan
Keyword(s):  
Body Weight ◽  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Weight Ratio ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Body Weight Ratio ◽  
Renal Hypertrophy ◽  
Protein Levels ◽  
Pai 1

Abstract Background and objective: ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type I repeats-13) cleaves von Willebrand factor (VWF), a large multimeric protein that plays an important role in hemostasis and thrombosis. Severe deficiency or very low levels of ADAMTS13 in presence of external stimuli results in accumulation of thrombogenic ultra large VWF multimers (which are released from activated endothelium) known to trigger thrombotic microangiopathy. Activated endothelium/dysfunction is a prominent feature of diabetic nephropathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy. Significantly reduced ADAMTS13 and increased plasma VWF levels have been found in diabetic patients with nephropathy. Although major site of ADAMTS13 synthesis is liver, ADAMTS13 is also expressed by podocytes in normal renal cortex. It remains unknown, however, whether VWF and ADAMTS13 imbalance plays a causal role in development of nephropathy in diabetic patients or rather is simply an associate marker of disease status, possibly secondary to endothelial function. We performed experiments in genetic models to determine whether ADAMTS13 and VWF axis contributes to diabetic nephropathy. Methods : Male, 8-10 weeks old wild-type (WT), Adamts13-/- and Vwf-/- mice were made diabetic by injecting multiple low doses of streptozotocin (60 mg/kg, i.p. for five consecutive days). Successful diabetes induction was tested after 2 weeks by measuring blood glucose. Mice having blood glucose levels above 300 mg/dL were included in the study. Controls were nondiabetic littermate mice treated with citrate buffer. The extent of renal injury was evaluated after 28 weeks of diabetes induction by measuring albuminuria and kidney to body weight ratio. Renal hypertrophy and extracellular matrix deposition was quantified by hematoxylin and immunostaining. PAI-1 mRNA and protein levels were measured by real time quantitative RT-PCR and ELISA. Results: Adamts13- /- diabetic mice exhibited significantly increased kidney to body weight ratio (P<0.05 vs. WT diabetic mice). Urine albuminuria, an index of renal injury was significantly elevated in Adamts13-/- diabetic mice (P<0.05 vs. WT diabetic mice). Increased renal injury in Adamts13-/- diabetic mice was concomitant with increased renal hypertrophy and extracellular matrix (ECM) deposition within glomeruli (P<0.05 vs. WT diabetic mice). Murine studies have shown that PAI-1 contributes to diabetic nephropathy by regulating TGF-beta and ECM deposition. A positive association exists between increased PAI-1 levels in glomeruli and microangiopathy in patients with diabetic nephropathy. We determined whether ADAMTS13 deficiency-induced microangiopathy in glomeruli increases PAI-1 levels. Adamts13-/- diabetic mice exhibited increased PAI-1 mRNA and protein levels (P<0.05 vs. WT diabetic mice). VWF remains the only known substrate of ADAMTS13 and increased plasma VWF levels have been associated with diabetic nephropathy. We determined the role of VWF in diabetic nephropathy. Vwf-/- diabetic mice exhibited significantly decreased kidney weight/body weight ratio, less urinary albuminuria, decreased kidney PAI-1 expression levels concomitant with improved kidney morphological changes (P<0.05 vs. WT diabetic mice). Conclusion : These findings provide experimental evidence for the first time that ADAMTS13/VWF axis potentially contributes to diabetic nephropathy, most likely by regulating PAI-1 levels. Disclosures No relevant conflicts of interest to declare.

scholarly journals ACE-modulated adiposity is related to higher energy expenditure and independent of lipolysis and glucose incorporation into lipids in adipocytes

2017 ◽  
Vol 49 (12) ◽  
pp. 712-721 ◽  
Author(s):  
Miriam Helena Fonseca-Alaniz ◽  
Talita Sayuri Higa ◽  
Tarcila Beatriz Ferraz-de-Campos ◽  
Julie Takada ◽  
Francisco Leonardo Torres-Leal ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Expenditure ◽  
Weight Control ◽  
Gene Dosage ◽  
Renin Angiotensin System ◽  
Gene Copy ◽  
Type I ◽  
Ace Gene ◽  
Gene Copies ◽  
Glucose Incorporation

Emerging evidence suggests that both systemic and white adipose tissue-renin-angiotensin system components influence body weight control. We previously demonstrated that higher angiotensin-converting enzyme (ACE) gene expression is associated with lower body adiposity in a rodent model. In this study, we tested the hypothesis that a higher ACE gene dosage reduces fat accumulation by increasing energy expenditure and modulating lipolysis and glucose incorporation into lipids in adipocytes. After a 12 wk follow-up period, transgenic mice harboring three ACE (3ACE) gene copies displayed diminished WAT mass, lipid content in their carcasses, adipocyte hypotrophy, and higher resting oxygen uptake (V̇o2) in comparison with animals with one ACE gene copy (1ACE) after long fasting (12 h). No differences were found in food intake and in the rates of lipolysis and glucose incorporation into lipids in adipocytes. To assess whether this response involves increased angiotensin II type I receptor (AT1R) activation, AT1R blocker (losartan) was used in a separate group of 3ACE mice with body weight and adiposity comparable to that in the other 3ACE animals. We suggest that fasting-induced lower adiposity observed in animals with 3ACE gene copies might be associated with a higher expense of energy reserves; this response did not involve AT1R activation.

scholarly journals Effects ofBauhinia forficataTea on Oxidative Stress and Liver Damage in Diabetic Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Andréia Caroline Fernandes Salgueiro ◽  
Vanderlei Folmer ◽  
Marianne Pires da Silva ◽  
Andreas Sebastian Loureiro Mendez ◽  
Ana Paula Pegoraro Zemolin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Body Weight ◽  
Liver Damage ◽  
Weight Ratio ◽  
Protein Carbonyl ◽  
Diabetic Mice ◽  
Body Weight Ratio ◽  
Glucose Levels ◽  
Nonprotein Thiols

This study was designed to evaluate the effects ofBauhinia forficataLink subsp.pruinosa(BF) tea on oxidative stress and liver damage in streptozotocin (STZ)-induced diabetic mice. Diabetic male mice have remained 30 days without any treatment. BF treatment started on day 31 and continued for 21 days as a drinking-water substitute. We evaluated (1) BF chemical composition; (2) glucose levels; (3) liver/body weight ratio and liver transaminases; (4) reactive oxygen species (ROS), lipid peroxidation, and protein carbonylation in liver; (5) superoxide dismutase (SOD) and catalase (CAT) activities in liver; (6)δ-aminolevulinate dehydratase (δ-ALA-D) and nonprotein thiols (NPSH) in liver; (7) Nrf2, NQO-1, and HSP70 levels in liver and pancreas. Phytochemical analyses identified four phenols compounds. Diabetic mice present high levels of NQO-1 in pancreas, increased levels of ROS and lipid peroxidation in liver, and decrease in CAT activity. BF treatment normalized all these parameters. BF did not normalize hyperglycemia, liver/body weight ratio, aspartate aminotransferase, protein carbonyl, NPSH levels, andδ-ALA-D activity. The raised oxidative stress seems to be a potential mechanism involved in liver damage in hyperglycemic conditions. Our results indicated that BF protective effect could be attributed to its antioxidant capacity, more than a hypoglycemic potential.

scholarly journals Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 41
Author(s):  
Nouf Aljobaily ◽  
Michael J. Viereckl ◽  
David S. Hydock ◽  
Hend Aljobaily ◽  
Tsung-Yen Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Methylation ◽  
Body Weight ◽  
Liver Fibrosis ◽  
Liver Damage ◽  
Cellular Senescence ◽  
Weight Ratio ◽  
Mrna Levels ◽  
Body Weight Ratio ◽  
Chromosomal Stability

Background: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Methods: Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. Results: The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.

Exercise and clenbuterol as strategies to decrease the progression of muscular dystrophy in mdx mice

1996 ◽  
Vol 80 (3) ◽  
pp. 734-741 ◽  
Author(s):  
E. E. Dupont-Versteegden
Keyword(s):  
Body Weight ◽  
Muscular Dystrophy ◽  
Weight Ratio ◽  
Morphological Characteristics ◽  
Mdx Mice ◽  
Body Weight Ratio ◽  
Muscle Weight ◽  
Sedentary Group ◽  
Running Activity ◽  
Tetanic Tension

The effects of exercise and the combination of exercise and clenbuterol on progression of muscular dystrophy were studied in mdx mice. At 3 wk of age, mdx mice were randomly assigned to sedentary (MS), exercise (ME), or combined exercise and clenbuterol (MEC) groups. Clenbuterol was given in the drinking water (1.0-1.5 mg . kg body weight-1 . day-1), and exercise consisted of spontaneous running activity on exercise wheels. At 3 mo or 1 yr of age, ventilatory function, contractile properties, and morphological characteristics of the soleus (Sol) and diaphragm (Dia) muscles were measured. The mdx mice receiving clenbuterol ran less than the mice without clenbuterol. The combination of clenbuterol and exercise was associated with an increase in Sol muscle weight and a muscle weight-to-body weight ratio of 30-35% compared with the sedentary group and approximately 20% compared to exercise alone. Myosin and total protein concentrations of the Sol and Dia increased in the MEC group at 1 yr of age only. Normalized active tension was increased in the Dia at 1 yr of age in both the ME and MEC groups by approximately 30%. Absolute tetanic tension of the Sol was increased at both 3 mo and 1 yr of age in the MEC compared with the MS group. At 1 yr of age, there was an additional 23% increase compared with the ME group. Fatigability increased in the MEC group by approximately 25% in the Sol and Dia muscles at both ages compared with the MS and ME groups. Results indicate that exercise and exercise plus clenbuterol decrease the progression of muscular dystrophy. However, different mechanisms may be involved because the combination of clenbuterol and exercise resulted in increased fatigability and the development of deformities, whereas exercise alone did not. Therefore, clenbuterol may not be suitable for use in patients with muscular dystrophy.

A study on the safety evaluation of buphrenorphine administered through an autoinjector compared with manual injection using haematological and biochemical variables in rats

2016 ◽  
Vol 36 (9) ◽  
pp. 901-909 ◽  
Author(s):  
D Sheela ◽  
R Vijayaraghavan ◽  
S Senthilkumar
Keyword(s):  
Body Weight ◽  
Research Work ◽  
Safety Evaluation ◽  
Weight Ratio ◽  
The Body ◽  
Control Group ◽  
Body Weight Ratio ◽  
Significant Difference ◽  
Manual Group ◽  
Significant Change

Buprenorphine drug cartridge was made for autoinjector device for use in emergency and critical situations to reduce the morbidity and mortality. Water-filled cartridges were prepared and buprenorphine was injected aseptically in the cartridge, to make 0.05 and 0.10 mg/mL. Rats were injected intraperitoneally, buprenorphine (0.3 and 0.6 mg/kg), repeatedly with the autoinjector and compared with manual injection (7 days and 14 days) using various haematological and biochemical parameters. No significant change was observed in the body weight, organ to body weight ratio and haematological variables in any of the experimental groups compared with the control group. Except serum urea and aspartate aminotransferase, no significant change was observed in glucose, cholesterol, triglycerides, bilirubin, protein, albumin, creatinine, uric acid, alanine aminotransferase, gamma glutamyltransferase and alkaline phosphatase. The autoinjectors deliver the drugs with spray effect and force for faster absorption. In the present study, the autoinjector meant for intramuscular injection was injected intraperitoneally in rats, and the drug was delivered with force on the vital organs. No significant difference was observed in the autoinjector group compared to the manual group showing tolerability and safety of the buphrenorphine autoinjector. This study shows that buprenorphine autoinjector can be considered for further research work.

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