scholarly journals Fenugreek Prevents the Development of STZ-Induced Diabetic Nephropathy in a Rat Model of Diabetes

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yingli Jin ◽  
Yan Shi ◽  
Yinggang Zou ◽  
Chunsheng Miao ◽  
Bo Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Rat Model ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Diabetic Rat ◽  
Dimethyl Formamide ◽  
Interventional Treatment ◽  
Morphological Alterations

The present study aims to examine the protective effect of fenugreek and the underlying mechanism against the development of diabetic nephropathy (DN) in streptozotocin- (STZ-) induced diabetic rats. A rat model of diabetes was successfully established by direct injection of STZ and then the rats were administered an interventional treatment of fenugreek. Parameters of renal function, including blood glucose, albuminuria, hemoglobin A1c (HbA1c), dimethyl formamide (DMF), blood urine nitrogen (BUN), serum creatinine (Scr), and kidney index (KI), were detected in the three groups (Con, DN, and DF). Oxidative stress was determined by the activity of antioxidase. Extracellular matrix (ECM) accumulation and other morphological alterations were evaluated by means of immunohistochemistry and electron microscope. Quantitive (q)PCR was employed to detect the mRNA expression of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) and protein expression was determined with western blot analysis. DN rats in the present study demonstrated a significant renal dysfunction, ECM accumulation, pathological alteration, and oxidative stress, while the symptoms were evidently reduced by fenugreek treatment. Furthermore, the upregulation of TGF-β1 and CTGF at a transcriptional and translational level in DN rats was distinctly inhibited by fenugreek. Consequently, fenugreek prevents DN development in a STZ-induced diabetic rat model.

scholarly journals Pterostilbene Attenuates Fructose-Induced Myocardial Fibrosis by Inhibiting ROS-Driven Pitx2c/miR-15b Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-25 ◽  
Author(s):  
Lin-Lin Kang ◽  
Dong-Mei Zhang ◽  
Rui-Qing Jiao ◽  
Shu-Man Pan ◽  
Xiao-Juan Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Myocardial Fibrosis ◽  
Transforming Growth Factor ◽  
Myocardial Hypertrophy ◽  
Tissue Growth ◽  
H9c2 Cells ◽  
High Fructose ◽  
Signaling Activation ◽  
Low Expression

Excessive fructose consumption induces oxidative stress and myocardial fibrosis. Antioxidant compound pterostilbene has cardioprotective effect in experimental animals. This study is aimed at investigating how fructose drove fibrotic responses via oxidative stress in cardiomyocytes and explored the attenuation mechanisms of pterostilbene. We observed fructose-induced myocardial hypertrophy and fibrosis with ROS overproduction in rats. Paired-like homeodomain 2 (Pitx2c) increase, microRNA-15b (miR-15b) low expression, and p53 phosphorylation (p-p53) upregulation, as well as activation of transforming growth factor-β1 (TGF-β1)/drosophila mothers against DPP homolog (Smads) signaling and connective tissue growth factor (CTGF) induction, were also detected in fructose-fed rat hearts and fructose-exposed rat myocardial cell line H9c2 cells. The results from p53 siRNA or TGF-β1 siRNA transfection showed that TGF-β1-induced upregulation of CTGF expression and p-p53 activated TGF-β1/Smads signaling in fructose-exposed H9c2 cells. Of note, Pitx2c negatively modulated miR-15b expression via binding to the upstream of the miR-15b genetic loci by chromatin immunoprecipitation and transfection analysis with pEX1-Pitx2c plasmid and Pitx2c siRNA, respectively. In H9c2 cells pretreated with ROS scavenger N-acetylcysteine, or transfected with miR-15b mimic and inhibitor, fructose-induced cardiac ROS overload could drive Pitx2c-mediated miR-15b low expression, then cause p-p53-activated TGF-β1/Smads signaling and CTGF induction in myocardial fibrosis. We also found that pterostilbene significantly improved myocardial hypertrophy and fibrosis in fructose-fed rats and fructose-exposed H9c2 cells. Pterostilbene reduced cardiac ROS to block Pitx2c-mediated miR-15b low expression and p-p53-dependent TGF-β1/Smads signaling activation and CTGF induction in high fructose-induced myocardial fibrosis. These results firstly demonstrated that the ROS-driven Pitx2c/miR-15b pathway was required for p-p53-dependent TGF-β1/Smads signaling activation in fructose-induced myocardial fibrosis. Pterostilbene protected against high fructose-induced myocardial fibrosis through the inhibition of Pitx2c/miR-15b pathway to suppress p-p53-activated TGF-β1/Smads signaling, warranting the consideration of Pitx2c/miR-15b pathway as a therapeutic target in myocardial fibrosis.

Mechanisms through which bradykinin promotes glomerular injury in diabetes

2005 ◽  
Vol 288 (3) ◽  
pp. F483-F492 ◽  
Author(s):  
Yan Tan ◽  
Bing Wang ◽  
Joo-Seob Keum ◽  
Ayad A. Jaffa
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Collagen I ◽  
Mrna Levels ◽  
Glomerular Injury ◽  
Western Blots ◽  
Protein Levels

In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B2 receptors (B2KR), connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and TGF-β type II receptor (TGF-βRII) and assessed the signaling mechanisms through which B2KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B2KR, CTGF, and TGF-β as well as protein levels of CTGF and TGF-βRII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B2KR and TGF-β mRNA levels expressed relative to β-actin mRNA levels and CTGF and TGF-βRII protein levels were significantly increased in D and D+I rats compared with C rats ( P < 0.03, n = 5). To assess the contribution of B2KR activation on modulating the expression of CTGF, TGF-βRII, and collagen I, mesangial cells (MC) were treated with BK (10−8 M) for 24 h and CTGF and TGF-βRII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-βRII protein levels was observed in response to BK stimulation ( P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10−8 M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK ( P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 μM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-βRII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10−8 M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-βRII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-βRII, and collagen I in MC and provide a mechanistic pathway through which B2KR activation may contribute to the development of diabetic nephropathy.

scholarly journals Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney

2001 ◽  
Vol 170 (3) ◽  
pp. 647-651 ◽  
Author(s):  
C Hill ◽  
A Flyvbjerg ◽  
R Rasch ◽  
M Bak ◽  
A Logan
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Western Blotting ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Human Monoclonal Antibody ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Diabetic Kidney ◽  
In The Diabetic Kidney

Diabetic nephropathy is characterised by an increase in glomerular and tubular fibrosis that compromises kidney function. The transforming growth factor-betas (TGF-betas) have been shown to play a major role in fibrosis and we have shown that TGF-beta2, in particular, increases co-ordinately with fibrogenesis in the diabetic kidney. The aim of this study was to investigate the changes in expression of extracellular matrix molecules in the diabetic kidney, with and without systemic administration of a recombinant human monoclonal antibody to TGF-beta2. Streptozotocin-induced diabetic rats were split into two groups. The first were treated with 5 mg/kg irrelevant control IgG4 (placebo) and the second treated with 5 mg/kg isoform-specific recombinant monoclonal anti-TGF-beta2 IgG4 (termed CAT-152) systemically every second day for 14 days. A further group of six non-diabetic rats was also used as a control. Various biological parameters were measured daily throughout the experimental period, and on termination of the experiment at 14 days Western blotting was performed on kidney cortices for procollagen-I C-propeptide, which is an indicator of the rate of collagen-I synthesis within the kidney. In the placebo-treated diabetic rats, blood glucose, food consumption, urinary albumin excretion (UAE) and kidney weights were all significantly higher than in the non-diabetic group (P<0.05, n=24, by ANOVA). In the anti-TGF-beta2-treated diabetic rats, kidney weights and UAE levels were decreased when compared with those in placebo-treated diabetics. Western blotting for the procollagen-I C-propeptide in kidney cortices showed a significant increase in levels in placebo-treated diabetic rats compared with non-diabetic controls over the 14 day diabetic period, indicating initiation of fibrogenesis. By contrast, in anti-TGF-beta2-treated diabetic rats, levels of the propeptide remained at non-diabetic levels. In summary, a significant suppression of kidney fibrosis was seen in anti-TGF-beta2-treated diabetic rats, compared with placebo-treated diabetic rats. We conclude that systemic delivery of CAT-152, a neutralising anti-TGF-beta2 antibody, during the acute stages of diabetic nephropathy reduces the rate of pathogenic fibrosis in the kidney.

scholarly journals Effects of Allicin on Pathophysiological Mechanisms during the Progression of Nephropathy Associated to Diabetes

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1134
Author(s):  
Abraham Said Arellano-Buendía ◽  
Luis Gerardo Castañeda-Lara ◽  
María L. Loredo-Mendoza ◽  
Fernando E. García-Arroyo ◽  
Pedro Rojas-Morales ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Glucose Transporter ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Tissue Growth ◽  
Kidney Cortex ◽  
Mesangial Matrix ◽  
Insulin Levels ◽  
The Impact

This study aimed to assess the impact of allicin on the course of diabetic nephropathy. Study groups included control, diabetes, and diabetes-treated rats. Allicin treatment (16 mg/kg day/p.o.) started after 1 month of diabetes onset and was administered for 30 days. In the diabetes group, the systolic blood pressure (SBP) increased, also, the oxidative stress and hypoxia in the kidney cortex were evidenced by alterations in the total antioxidant capacity as well as the expression of nuclear factor (erythroid-derived 2)-like 2/Kelch ECH associating protein 1 (Nrf2/Keap1), hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin (Epo) and its receptor (Epo-R). Moreover, diabetes increased nephrin, and kidney injury molecule-1 (KIM-1) expression that correlated with mesangial matrix, the fibrosis index and with the expression of connective tissue growth factor (CTGF), transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA). The insulin levels and glucose transporter protein type-4 (GLUT4) expression were decreased; otherwise, insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) expression was increased. Allicin increased Nrf2 expression and decreased SBP, Keap1, HIF-1α, and VEGF expression. Concurrently, nephrin, KIM-1, the mesangial matrix, fibrosis index, and the fibrotic proteins were decreased. Additionally, allicin decreased hyperglycemia, improved insulin levels, and prevented changes in (GLUT4) and IRSs expression induced by diabetes. In conclusion, our results demonstrate that allicin has the potential to help in the treatment of diabetic nephropathy. The cellular mechanisms underlying its effects mainly rely on the regulation of antioxidant, antifibrotic, and antidiabetic mechanisms, which can contribute towards delay in the progression of renal disease.

scholarly journals Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 12963
Author(s):  
Mónika Gabriella Kovács ◽  
Zsuzsanna Z. A. Kovács ◽  
Zoltán Varga ◽  
Gergő Szűcs ◽  
Marah Freiwan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Growth Factor ◽  
Rat Model ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Sprague Dawley ◽  
Radiation Induced

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model.

scholarly journals Streptozocin Diabetes Elevates all Isoforms of TGF-β in the Rat Kidney

2001 ◽  
Vol 2 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Pascale H. Lane ◽  
Dustin M. Snelling ◽  
William J. Langer
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Fold Increase ◽  
Diabetic Rat ◽  
The Impact ◽  
Tgf Β1

Transforming growth factor beta (TGF-β) is a major promoter of diabetic nephropathy. While TGF-β1 is the most abundaft renal isoform, types 2 and 3 are present as well and have identicalin vitroeffects. Whole kidney extracts were studied 2 weeks after induction of streptozocin diabetes and in control rats. Mean glomerular area was 25% greater in the diabetic animals. TGF-β1 showed a 2-fold increase in message with a 3-fold increase in protein. TGF-β2 mRNA increased approximately 6% while its protein doubled. TGF-β-message increased by 25%, producing a 35% increase in its protein. TGF-β- inducible gene H3 mRNA was increased 35% in the diabetic animals, consistent with increased activity of this growth factor. All isoforms of TGF-β are increased in the diabetic rat kidney. Future studies need to address the specific role that each isoform plays in diabetic nephropathy as well as the impact of therapies on each isoform.

Allium jesdianum hydro alcoholic extract ameliorates diabetic nephropathy by suppressing connective tissue growth factor (CTGF) and receptor for advanced glycation endproducts (RAGE) gene expression in diabetic rats with streptozotocin

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mona Alaee ◽  
Jamal Amri ◽  
Hadi Karami ◽  
Seyed Amirhossein Latifi ◽  
Zahra Salemi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Advanced Glycation Endproducts ◽  
Diabetic Rats ◽  
Tissue Growth ◽  
Serum Urea ◽  
Advanced Glycation ◽  
Glycation Endproducts

Abstract Objectives Diabetic nephropathy is one of the major complications of diabetes, the use of medicinal plants is increasing due to fewer side effects. This study was designed to examine antidiabetic effects of Allium jesdianum (A. jesdianum) ethanolic extract and evaluate its effects on oxidative stress markers and the expression of connective tissue growth factor (CTGF) and receptor for advanced glycation endproducts (RAGE) genes in the kidney of type 1 diabetic rats. Methods In this study, we randomly divided 24 rats into four groups with six rats in each group as follows: Cnt group: normal control receiving normal saline, Dibt group: diabetic control receiving normal saline daily, Dibt + A. jesdianum 250 group: diabetic rats receiving A. jesdianum at a dose of 250 mg/kg bw daily, Dibt + A. jesdianum 500 group: diabetic rats receiving A. jesdianum at a dose of 500 mg/kg bw daily. To induce diabetes, we used 55 mg/kg bw dose of streptozotocin intraperitoneally. The concentration of fasting blood glucose (FBG) and serum urea, creatinine and albumin, SOD, MDA (using spectrophotometric methods) and gene expression of CTGF and RAGE in kidney tissue (using real-time PCR methods) were quantified in the diabetic rats that received A. jesdianum for 42 days, and were compared to control rats. Results The results showed that in the diabetic group the FBG and serum urea, creatinine and expression of kidney CTGF and RAGE genes and the levels of SOD and MDA significantly increased and serum albumin significantly decreased compared to the Cnt group (p<0.001). Administration of A. jesdianum significantly improved the FBG and serum urea, creatinine and albumin compared to Dibt group (p<0.05). It was shown the A. jesdianum significantly decrease the kidney expression levels of CTGF and RAGE genes and improve oxidative stress (increased SOD and decreased MDA) in the kidney tissues when compared to Dibt group (p<0.001). Also, it was found that the beneficial effects of the A. jesdianum were dose-dependent. Conclusions The results of this study showed that administration of A. jesdianum for 42 days has beneficial anti-diabetic and anti-nephropathic effects in diabetic rats and can be used as an adjunct therapy in the treatment of diabetes.

scholarly journals Sulforaphane Attenuation of Type 2 Diabetes-Induced Aortic Damage Was Associated with the Upregulation of Nrf2 Expression and Function

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yonggang Wang ◽  
Zhiguo Zhang ◽  
Wanqing Sun ◽  
Yi Tan ◽  
Yucheng Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Related Factor ◽  
Pathological Changes ◽  
And Function ◽  
Nrf2 Expression

Type 2 diabetes mellitus (T2DM) significantly increases risk for vascular complications. Diabetes-induced aorta pathological changes are predominantly attributed to oxidative stress. Nuclear factor E2-related factor-2 (Nrf2) is a transcription factor orchestrating antioxidant and cytoprotective responses to oxidative stress. Sulforaphane protects against oxidative damage by increasing Nrf2 expression and its downstream target genes. Here we explored the protective effect of sulforaphane on T2DM-induced aortic pathogenic changes in C57BL/6J mice which were fed with high-fat diet for 3 months, followed by a treatment with streptozotocin at 100 mg/kg body weight. Diabetic and nondiabetic mice were randomly divided into groups with and without 4-month sulforaphane treatment. Aorta of T2DM mice exhibited significant increases in the wall thickness and structural derangement, along with significant increases in fibrosis (connective tissue growth factor and transforming growth factor), inflammation (tumor necrosis factor-αand vascular cell adhesion molecule 1), oxidative/nitrative stress (3-nitrotyrosine and 4-hydroxy-2-nonenal), apoptosis, and cell proliferation. However, these pathological changes were significantly attenuated by sulforaphane treatment that was associated with a significant upregulation of Nrf2 expression and function. These results suggest that sulforaphane is able to upregulate aortic Nrf2 expression and function and to protect the aorta from T2DM-induced pathological changes.

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