Angiotensin blockade attenuates diabetic nephropathy in hypogonadal adult male rats

2019 ◽  
Vol 97 (8) ◽  
pp. 708-720
Author(s):  
Samy Makary ◽  
Mohamed Abdo ◽  
Wael Abdo Hassan ◽  
Mona K. Tawfik
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Angiotensin Ii ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Male Rats ◽  
Glomerular Hypertrophy ◽  
Necrosis Factor Alpha ◽  
Angiotensin Blockade ◽  
And Oxidative Stress

This study examined the effect of the aromatase inhibitor letrozole (0.5 mg/kg) alone or in combination with the angiotensin-receptor blocker valsartan (30 mg/kg) against streptozocin-induced diabetic nephropathy (DN) in hypogonadal (HG) rats for 12 weeks. First, we tested the HG effect on hormone levels, inflammatory cytokines, and oxidative stress in nondiabetic (ND) and diabetic (D) rats. HG was induced with the luteinizing hormone-releasing hormone antagonist cetrorelix (0.71 mg/kg). Diabetes enhanced hormonal hypogonadism and increased inflammation and oxidative stress. Next, experiments examined the effect of early letrozole and valsartan intervention on DN in HG rats. HG-ND and HG-D rats were treated with letrozole alone or in combination with valsartan. HG-D rats developed proteinuria and had increased blood urea nitrogen and creatinine, and histopathological evidence of renal injury, including glomerular hypertrophy and mesangial expansion. Valsartan alone or in combination with letrozole reduced proteinuria, improved renal functions, and reduced diabetes-induced renal angiotensin II. Both agents ameliorated nuclear factor kappa light chain enhancer of activated B cells, interleukin 1β, interleukin 6, and tumor necrosis factor alpha levels. The combination decreased superoxide dismutase, malondialdehyde, and glutathione peroxidase levels, and prevented glomerular hypertrophy. In HG-D rats, valsartan reduced renal collagen IV and transforming growth factor-beta 1, especially when the testosterone level was corrected by letrozole. Thus, normalizing testosterone and inhibiting renal angiotensin II have a renoprotective effect against DN in HG male rats.

scholarly journals Role of endocannabinoid CB1 receptors in Streptozotocin-induced uninephrectomised Wistar rats in diabetic nephropathy

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Jayarami Reddy Medapati ◽  
Deepthi Rapaka ◽  
Veera Raghavulu Bitra ◽  
Santhosh Kumar Ranajit ◽  
Girija Sankar Guntuku ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Morphological Changes ◽  
Serum Levels ◽  
Cb1 Receptors ◽  
Protective Effects ◽  
Renal Hypertrophy ◽  
Necrosis Factor Alpha

Abstract Background The endocannabinoid CB1 receptor is known to have protective effects in kidney disease. The aim of the present study is to evaluate the potential agonistic and antagonistic actions and to determine the renoprotective potential of CB1 receptors in diabetic nephropathy. The present work investigates the possible role of CB1 receptors in the pathogenesis of diabetes-induced nephropathy. Streptozotocin (STZ) (55 mg/kg, i.p., once) is administered to uninephrectomised rats for induction of experimental diabetes mellitus. The CB1 agonist (oleamide) and CB1 antagonist (AM6545) treatment were initiated in diabetic rats after 1 week of STZ administration and were given for 24 weeks. Results The progress in diabetic nephropathy is estimated biochemically by measuring serum creatinine (1.28±0.03) (p < 0.005), blood urea nitrogen (67.6± 2.10) (p < 0.001), urinary microprotein (74.62± 3.47) (p < 0.005) and urinary albuminuria (28.31±1.17) (p < 0.0001). Renal inflammation was assessed by estimating serum levels of tumor necrosis factor alpha (75.69±1.51) (p < 0.001) and transforming growth factor beta (8.73±0.31) (p < 0.001). Renal morphological changes were assessed by estimating renal hypertrophy (7.38± 0.26) (p < 0.005) and renal collagen content (10.42± 0.48) (p < 0.001). Conclusions From the above findings, it can be said that diabetes-induced nephropathy may be associated with overexpression of CB1 receptors and blockade of CB1 receptors might be beneficial in ameliorating the diabetes-induced nephropathy. Graphical abstract

scholarly journals The Attenuation of Moutan Cortex on Oxidative Stress for Renal Injury in AGEs-Induced Mesangial Cell Dysfunction and Streptozotocin-Induced Diabetic Nephropathy Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Minghua Zhang ◽  
Liang Feng ◽  
Junfei Gu ◽  
Liang Ma ◽  
Dong Qin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Cell Dysfunction ◽  
Moutan Cortex

Oxidative stress (OS) has been regarded as one of the major pathogeneses of diabetic nephropathy (DN) through damaging kidney which is associated with renal cells dysfunction. The aim of this study was to investigate whether Moutan Cortex (MC) could protect kidney function against oxidative stressin vitroorin vivo. The compounds in MC extract were analyzed by HPLC-ESI-MS. High-glucose-fat diet and STZ (30 mg kg−1) were used to induce DN rats model, while 200 μg mL−1AGEs were for HBZY-1 mesangial cell damage. The treatment with MC could significantly increase the activity of SOD, glutathione peroxidase (GSH-PX), and catalase (CAT). However, lipid peroxidation malondialdehyde (MDA) was reduced markedlyin vitroorin vivo. Furthermore, MC decreased markedly the levels of blood glucose, serum creatinine, and urine protein in DN rats. Immunohistochemical assay showed that MC downregulated significantly transforming growth factor beta 2 (TGF-β2) protein expression in renal tissue. Our data provided evidence to support this fact that MC attenuated OS in AGEs-induced mesangial cell dysfunction and also in high-glucose-fat diet and STZ-induced DN rats.

scholarly journals Prognosis of progression of chronic generalised periodontitis in patients with bronchiectatic disease

2020 ◽  
Vol 27 (1) ◽  
pp. 72-84
Author(s):  
Artem K. Sarkisov ◽  
Vladimir A. Zelenskiy ◽  
Ekaterina A. Polunina ◽  
Karen A. Sarkisov
Keyword(s):  
Oxidative Stress ◽  
Mathematical Model ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Binary Logistic Regression ◽  
Control Group ◽  
Healthy Individuals ◽  
Logistic Regression Method ◽  
High Level ◽  
And Oxidative Stress

Aim. To analyse the parameters of dental indices and the level of markers of infl ammation and oxidative stress in patients with chronic generalised periodontitis (CGP) with bronchiectatic disease and to develop a mathematical model for assessing the risk of CGP progression in patients with bronchiectatic disease.Materials and methods. A total of 70 patients with mild and moderate CGP were examined, which were divided into the following groups: patients with CGP without general somatic pathology (n = 33), and patients with CGP and bronchiectatic disease (n = 37). The control group consisted of somatically healthy individuals with intact periodontium (n = 40). Dental indices (PMA, PI, Muhlemann, OHI-s), infl ammatory markers (transforming growth factor beta 1 (TGFβ-1), lactoferrin (LF), interleukin-8 (IL-8), C — reactive protein (CRP)), and oxidative stress markers (malondialdehyde (MDA), as well as advanced oxidation protein products (AOPPs), and total superoxide dismutase (SOD)) were analysed in all patients included in the study. The method of binary logical regression was used to create a mathematical model for assessing the risk of CGP progression in patients with bronchiectatic disease.Results. Dental indices and the level of markers of infl ammation and oxidative stress were statistically signifi cantly higher in all patients with CGP as compared to somatically healthy individuals, as well as in patients with CGP and bronchiectatic disease as compared to patients with CGP without general somatic pathology. Positive correlations of different strength between the studied markers of infl ammation and oxidative stress and dental indices were revealed. Based on the results of the correlation matrix data and using the binary logistic regression method, a mathematical model was developed that can be applied for assessing the risk of CGP progression in patients with bronchiectatic disease. The predictors of progression included in the mathematical model were: PI, TGFβ-1 and AOPPs. Conclusion. The data obtained indicate a greater severity of infl ammation and oxidative stress in CGP patients with comorbid pathology in the form of bronchiectatic disease and the infl uence of these processes on the periodontal condition. The proposed mathematical model for assessing the risk of CGP progression in patients with bronchiectatic disease is characterized by a high level of sensitivity and prognostic signifi cance, thus being applicable for use in clinical practice. 

scholarly journals The TGFβ1 Receptor Antagonist GW788388 Reduces JNK Activation and Protects Against Acetaminophen Hepatotoxicity in Mice

2019 ◽  
Vol 170 (2) ◽  
pp. 549-561 ◽  
Author(s):  
Matthew McMillin ◽  
Stephanie Grant ◽  
Gabriel Frampton ◽  
Anca D Petrescu ◽  
Elaina Williams ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Growth Factor ◽  
Liver Injury ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Growth Factor Beta ◽  
And Oxidative Stress

Abstract Acute liver failure is a serious consequence of acetaminophen (APAP)-induced hepatotoxic liver injury with high rates of morbidity and mortality. Transforming growth factor beta 1 (TGFβ1) is elevated during liver injury and influences hepatocyte senescence during APAP-induced hepatotoxicity. This study investigated TGFβ1 signaling in the context of inflammation, necrotic cell death, and oxidative stress during APAP-induced liver injury. Male C57Bl/6 mice were injected with 600 mg/kg APAP to generate liver injury in the presence or absence of the TGFβ receptor 1 inhibitor, GW788388, 1 h prior to APAP administration. Acetaminophen-induced liver injury was characterized using histological and biochemical measures. Transforming growth factor beta 1 expression and signal transduction were assessed using immunohistochemistry, Western blotting and ELISA assays. Hepatic necrosis, liver injury, cell proliferation, hepatic inflammation, and oxidative stress were assessed in all mice. Acetaminophen administration significantly induced necrosis and elevated serum transaminases compared with control mice. Transforming growth factor beta 1 staining was observed in and around areas of necrosis with phosphorylation of SMAD3 observed in hepatocytes neighboring necrotic areas in APAP-treated mice. Pretreatment with GW788388 prior to APAP administration in mice reduced hepatocyte cell death and stimulated regeneration. Phosphorylation of SMAD3 was reduced in APAP mice pretreated with GW788388 and this correlated with reduced hepatic cytokine production and oxidative stress. These results support that TGFβ1 signaling plays a significant role in APAP-induced liver injury by influencing necrotic cell death, inflammation, oxidative stress, and hepatocyte regeneration. In conclusion, targeting TGFβ1 or downstream signaling may be a possible therapeutic target for the management of APAP-induced liver injury.

scholarly journals Juglone Suppresses Inflammation and Oxidative Stress in Colitis Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuai Chen ◽  
Xin Wu ◽  
Zengli Yu
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Cytokines ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Activity Index ◽  
Uncoupling Protein ◽  
Vehicle Group ◽  
Related Factor ◽  
Mitochondrial Uncoupling ◽  
And Oxidative Stress

Juglone (JUG), a natural product found in walnut trees and other plants, shows potent antioxidant, antimicrobial, and immunoregulatory activities. However, it remains unknown whether JUG can alleviate ulcerative colitis. This study aims to explore the effect of JUG on dextran sulfate sodium (DSS)-induced colitis in mice. The mice were randomly assigned into three groups: the vehicle group, the DSS group, and the JUG group. The experiments lasted for 17 days; during the experiment, all mice received dimethyl sulfoxide (DMSO, 0.03% v/v)-containing water, while the mice in the JUG group received DMSO-containing water supplemented with JUG (0.04 w/v). Colitis was induced by administering DSS (3% w/v) orally for 10 consecutive days. The results showed that the JUG treatment significantly ameliorated body weight loss and disease activity index and improved the survival probability, colon length, and tissue damage. JUG reversed the DSS-induced up-regulation of proinflammatory cytokines, including interleukin (IL)-6, 12, 21, and 23, and tumor necrosis factor-alpha, and anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta, in the serum of the colitis mice. Additionally, the activation of mitochondrial uncoupling protein 2 and phospho-Nuclear Factor-kappa B p65 and the inhibition of the kelch-like ECH-associated protein 1 and NF-E2-related factor 2 induced by DSS were also reversed under JUG administration. Although the JUG group possessed a similar microbial community structure as the DSS group, JUG enriched potential beneficial microbes such as Lachnospiraceae_NK4A136_group but not pathogens such as Escherichia Shigella, which was dominative in DSS group, at the genus level. In conclusion, our results demonstrated that JUG could be a promising agent for UC prevention to regulate inflammatory cytokines and oxidative stress.

scholarly journals The effects of selenium supplementation on biomarkers of inflammation and oxidative stress in patients with diabetic nephropathy: a randomised, double-blind, placebo-controlled trial

2016 ◽  
Vol 116 (7) ◽  
pp. 1222-1228 ◽  
Author(s):  
Fereshteh Bahmani ◽  
Mahsa Kia ◽  
Alireza Soleimani ◽  
Ali Akbar Mohammadi ◽  
Zatollah Asemi
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Controlled Trial ◽  
Matrix Metalloproteinase 2 ◽  
Controlled Clinical Trial ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Hs Crp ◽  
And Oxidative Stress

AbstractThis study was carried out to assess the effects of Se supplementation on biomarkers of inflammation and oxidative stress in patients with diabetic nephropathy (DN). This randomised, double-blind, placebo-controlled clinical trial was conducted among sixty patients with DN. Patients were randomly divided into two groups to take either 200 µg/d Se supplements as Se yeast (n 30) or placebo (n 30) for 12 weeks. In unadjusted analyses, compared with the placebo, Se supplementation led to a significant reduction in high-sensitivity C-reactive protein (hs-CRP) (−1069·2 (sd 1752·2) v. −135·3 (sd 1258·9) ng/ml, P=0·02), matrix metalloproteinase-2 (MMP-2) (−612·3 (sd 679·6) v. +76·0 (sd 309·1) ng/ml, P<0·001) and plasma malondialdehyde (MDA) concentrations (−0·1 (sd 0·7) v. +0·4 (sd 0·9) µmol/l, P=0·01). In addition, a significant increase in plasma total antioxidant capacity (TAC) (+174·9 (sd 203·9) v. +15·8 (sd 382·2) mmol/l, P=0·04) was observed following supplementation with Se compared with the placebo. Subjects who received Se supplements experienced a borderline statistically significant decrease in serum protein carbonyl (PCO) levels (P=0·06) compared with the placebo. When we adjusted the analysis for baseline values of biochemical parameters, age and BMI, serum hs-CRP (P=0·14) and MDA levels (P=0·16) became non-significant, whereas plasma nitric oxide (NO) (P=0·04) and glutathione (GSH) (P<0·001) became statistically significant, and other findings did not change. Supplementation with Se had no significant effect on NO, transforming growth factor β (TGF-β), advanced glycation end products (AGE), PCO and GSH compared with the placebo. Overall, our study demonstrated that Se supplementation among DN patients had favourable effects on serum MMP-2, plasma NO, TAC and GSH, but did not affect hs-CRP, TGF-β, AGE, PCO and MDA.

Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters

2010 ◽  
Vol 299 (6) ◽  
pp. F1328-F1338 ◽  
Author(s):  
Yasutaka Maeda ◽  
Toyoshi Inoguchi ◽  
Ryoko Takei ◽  
Fumi Sawada ◽  
Shuji Sasaki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Angiotensin Ii ◽  
Renal Dysfunction ◽  
Transforming Growth Factor ◽  
Renin Angiotensin System ◽  
Transforming Growth Factor Β ◽  
Pathophysiological Role ◽  
Chymase Inhibitor

Accumulating evidence suggests that the intrarenal renin-angiotensin system may be involved in the progression of diabetic nephropathy. Chymase is a potent local angiotensin II-forming enzyme in several species, including humans and hamsters. However, the pathophysiological role of chymase is not fully understood. Here, we report a causal role of chymase in diabetic nephropathy and the therapeutic effectiveness of chymase inhibition. In the present study, renal chymase expression was markedly upregulated in streptozotocin-induced diabetic hamsters. Oral administration of a specific chymase inhibitor, TEI-F00806, completely ameliorated proteinuria, the overexpression of transforming growth factor-β and fibronectin in glomeruli, and renal mesangial expansion, by normalizing the increase in intrarenal angiotensin II levels in diabetic hamsters independently of blood pressure levels. In contrast, ramipril did not show such sufficient effects. These effects occurred in parallel with improvements in superoxide production and expression of NAD(P)H oxidase components [NAD(P)H oxidase 4 and p22 phox] in glomeruli. This study showed for the first time that chymase inhibition may protect against elevated intrarenal angiotensin II levels, oxidative stress, and renal dysfunction in diabetes. These findings suggest that chymase offers a new therapeutic target for diabetic nephropathy.

scholarly journals Vascular Cells Proteome Associated with Bradykinin and Leptin Inflammation and Oxidative Stress Signals

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1251
Author(s):  
Moustafa Al Hariri ◽  
Miran A. Jaffa ◽  
Richard Saoud ◽  
Jingfu Zhao ◽  
Rui Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Leptin Receptor ◽  
Transforming Growth Factor ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β ◽  
Protein Abundance ◽  
Plasminogen Activator Inhibitor 1 ◽  
Necrosis Factor Alpha ◽  
Stress Signals ◽  
And Oxidative Stress

Among the primary contributors to cardiovascular diseases are inflammation and oxidative imbalance within the vessel walls as well as the fibrosis of rat aortic smooth muscle cell (RASMC). Bradykinin (BK) and leptin are inflammatory modulators that are linked to vascular injury. In this study, we employed tandem LC-MS/MS to identify protein signatures that encompass protein abundance in RASMC treated with BK or leptin followed by systems biology analyses to gain insight into the biological pathways and processes linked to vascular remodeling. In the study, 1837 proteins were identified in control untreated RASMC. BK altered the expression of 72 (4%) and 120 (6.5%) proteins, whereas leptin altered the expression of 189 (10.2%) and 127 (6.5%) proteins after 24 and 48 h, respectively, compared to control RASMC. BK increased the protein abundance of leptin receptor, transforming growth factor-β. On the other hand, leptin increased the protein abundance of plasminogen activator inhibitor 1 but decreased the protein abundance of cofilin. BK and leptin induced the expression of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) and pathway analysis revealed the activation of mitogen-activated protein kinases (MAPKs) and AKT pathways. The proteome profile in response to BK and leptin revealed mechanistic interplay of multiple processes that modulate inflammation and oxidative stress signals in the vasculature.

scholarly journals Transforming Growth Factor-Beta and Oxidative Stress Interplay: Implications in Tumorigenesis and Cancer Progression

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Jelena Krstić ◽  
Drenka Trivanović ◽  
Slavko Mojsilović ◽  
Juan F. Santibanez
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Careful Consideration ◽  
Cancer Therapies ◽  
Antitumor Effects ◽  
Growth Factor Beta ◽  
And Oxidative Stress

Transforming growth factor-beta (TGF-β) and oxidative stress/Reactive Oxygen Species (ROS) both have pivotal roles in health and disease. In this review we are analyzing the interplay between TGF-βand ROS in tumorigenesis and cancer progression. They have contradictory roles in cancer progression since both can have antitumor effects, through the induction of cell death, senescence and cell cycle arrest, and protumor effects by contributing to cancer cell spreading, proliferation, survival, and metastasis. TGF-βcan control ROS production directly or by downregulating antioxidative systems. Meanwhile, ROS can influence TGF-βsignaling and increase its expression as well as its activation from the latent complex. This way, both are building a strong interplay which can be taken as an advantage by cancer cells in order to increment their malignancy. In addition, both TGF-βand ROS are able to induce cell senescence, which in one way protects damaged cells from neoplastic transformation but also may collaborate in cancer progression. The mutual collaboration of TGF-βand ROS in tumorigenesis is highly complex, and, due to their differential roles in tumor progression, careful consideration should be taken when thinking of combinatorial targeting in cancer therapies.

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