Angiotensin-(1–7) attenuates diabetic nephropathy in Zucker diabetic fatty rats

2012 ◽  
Vol 302 (12) ◽  
pp. F1606-F1615 ◽  
Author(s):  
Jorge F. Giani ◽  
Valeria Burghi ◽  
Luciana C. Veiras ◽  
Analía Tomat ◽  
Marina C. Muñoz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Renal Fibrosis ◽  
Hypoxia Inducible Factor ◽  
Thiobarbituric Acid ◽  
Zucker Rats ◽  
Tnf Α ◽  
Zucker Diabetic Fatty Rats

Angiotensin (ANG)-(1–7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1–7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1–7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1–7) (100 ng·kg−1·min−1) ( n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1–7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1–7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1–7). Chronic ANG-(1–7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1–7) emerges as a novel target for treatment of diabetic nephropathy.

Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats

2014 ◽  
Vol 307 (10) ◽  
pp. F1123-F1131 ◽  
Author(s):  
Giovanna Castoldi ◽  
Cira R. T. di Gioia ◽  
Camila Bombardi ◽  
Silvia Maestroni ◽  
Raffaella Carletti ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Fibrosis ◽  
Macrophage Infiltration ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Zucker Diabetic Fatty Rats ◽  
Compound 21 ◽  
Zdf Rats ◽  
Losartan Treatment

The aim of this study was to evaluate the effect of compound 21 (C21), a selective AT2 receptor agonist, on diabetic nephropathy and the potential additive effect of C21, when associated with losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The experiments lasted 15 wk (from 5 to 20 wk of age) and were performed in 40 ZDF rats and 12 control lean rats. ZDF rats were divided into 4 groups: 1) 9 rats were treated with losartan; 2) 10 rats were treated with C21; 3) 9 rats were treated with losartan plus C21; and 4) 12 rats were maintained without any treatment. ZDF rats showed an increase in blood glucose level, albuminuria, renal fibrosis, macrophage infiltration, and TNF-α expression and a reduction of glomerular nephrin expression compared with control lean rats. C21 treatment reduced renal glomerular, tubulointerstitial, and perivascular fibrosis, and macrophage infiltration and TNF-α expression in ZDF rats. C21 treatment caused a decrease in albuminuria in ZDF rats up to 11 wk of age. Losartan decreased macrophage infiltration, TNF-α expression, and renal glomerular and perivascular fibrosis, restored glomerular nephrin expression, but did not affect tubulointerstitial fibrosis. Losartan treatment caused a decrease in albuminuria in ZDF rats up to 15 wk of age. At the end of the protocol, only the combination of C21 plus losartan significantly reduced albuminuria in ZDF rats. These data demonstrate that C21 has beneficial effects on diabetic nephropathy, suggesting the combination of C21 and losartan as a novel pharmacological tool to slow the progression of nephropathy in type II diabetes.

scholarly journals Whole grain consumption has a modest effect on the development of diabetes in the Goto–Kakisaki rat

2011 ◽  
Vol 107 (2) ◽  
pp. 192-201 ◽  
Author(s):  
Moonyeon Youn ◽  
A. Saari Csallany ◽  
Daniel D. Gallaher
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Cell Mass ◽  
Thiobarbituric Acid ◽  
Basal Diet ◽  
Whole Grains ◽  
Whole Grain ◽  
Wheat Group ◽  
Basal Group

Epidemiological evidence suggests that whole grain intake is associated with reduced risk of type 2 diabetes. However, studies of individual whole grains on the prevention of type 2 diabetes are lacking. The objective of the present study was to examine the effect of different whole grains on type 2 diabetes in an animal model of type 2 diabetes, the Goto–Kakisaki (GK) rat. GK rats were fed either a basal diet or a whole grain-containing diet for 5 months. Whole grain diets contained 65 % whole grain flours of wheat, barley, oats or maize. After 2 months of feeding, fasting plasma glucose concentrations were lower in the wheat, barley and oats groups, compared with the basal group, whereas glycated Hb was significantly greater in the wheat group compared with other groups. Feeding of whole barley and maize increased plasma C-peptide concentrations compared with whole wheat at 2 months. There was a trend in the improvement of insulin resistance with a consumption of barley and oats diets at 2 months (P = 0·06) compared with the basal diet. Oxidative stress markers, urinary thiobarbituric acid-reactive substances and 8-isoprostane, did not improve with whole grain intake at 2 months. At 5 months, whole grain diets did not differ from the basal diet in glycaemic control, insulin secretion, oxidative stress and preservation of pancreatic β-cell mass. These results suggest that the consumption of whole grains may offer modest benefit early in the development of type 2 diabetes, but this benefit is lost with further development of the disease.

scholarly journals Oxidative stress and other risk factors associated with diabetic nephropathy in type 2 diabetes mellitus

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Snežana Mališ Mališ ◽  
Ana Savić Radojević ◽  
Marijana Kovačević ◽  
Olivera Čančar ◽  
Dragana Pavlović Pavlović ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Type 2 Diabetes ◽  
Uric Acid ◽  
Diabetic Nephropathy ◽  
Antioxidant Enzyme ◽  
Enzyme Activities ◽  
Antioxidant Enzyme Activities ◽  
Patient Age

Introduction. The aim of the study was to examine whether biomarkersof oxidative stress and antioxidant enzyme activities are among other riskfactors for diabetic nephropathy (DN).Methods. The study involved 70 patients with type 2 diabetes (37 males,aged 41 to 81 years) allocated to two groups: one of 32 patients with DNand the other of 38 patients without DN. In the study of oxidative stress 15healthy persons were included. All examined patients were interviewed andunderwent objective examination. Their serum and urine samples were analyzedin order to estimate the quality of glycoregulation and kidney function.Protein thiol groups (P-SH), antioxidant enzyme activities [superoxidedismutase (SOD) and glutathione peroxidase (GPX)] were determined inplasma spectrophotometrically and malondialdehyde-adducts (MDA) byenzyme immunoassay.Results. No significant differences were found between the two groupsfor demographic characteristics, duration and treatment of diabetes, bloodpressure, fasting glucose level and HbA1c. Patients with DN had a higherbody mass index, lower estimated glomerular filtration rate (eGFR) andhigher albuminuria and proteinuria. Plasma activity of GPX and SOD as wellas levels of MDA adducts and P-SH groups were similar in patients with andwithout DN, but GPX and SOD plasma activities were significantly lower andplasma level of MDA significantly higher in all patients than in healthy controls.Patient gender, age, BMI, HbA1c and plasma level of P-SH and MDAwere selected as significant predictors of DN. Patient age, duration of diabetes,serum phosphorus, uric acid levels and plasma SOD activity were negativelyassociated with eGFR. Patient age, serum levels of protein and albuminand plasma GPX activity were negatively, while systolic BP, serum levelsof uric acid and cholesterol were positively associated with proteinuria.Conclusion. Biomarkers of oxidative protein and lipid damage were selectedas risk factors for DN, besides several other well known risk factors.

scholarly journals Protective Effect of Hydroxysafflor Yellow A on Nephropathy by Attenuating Oxidative Stress and Inhibiting Apoptosis in Induced Type 2 Diabetes in Rat

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Maosheng Lee ◽  
Hengxia Zhao ◽  
Xuemei Liu ◽  
Deliang Liu ◽  
Jianping Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Western Blot ◽  
Protective Effect ◽  
Caspase 3 ◽  
Renal Tissue ◽  
Hydroxysafflor Yellow A

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and its prevalence has been increasing all over the world, which is also the leading cause of end-stage renal failure. Hydroxysafflor yellow A (HSYA) is the main active chemical component of Carthamus tinctorius L., and it is commonly used in patients with cardiovascular and cerebrovascular diseases in China. The aim of this study was to investigate the renal protective effects and molecular mechanisms of HSYA on high-fat diet (HFD) and streptozotocin- (STZ-) induced DN in rats. The DN rats were treated with HSYA for eight weeks. We assessed creatinine (CR), urea nitrogen (UN), glomerular volume, podocyte number, renal inflammation, oxidative stress, and cells apoptosis markers after HSYA treatment. The number of apoptotic cells was measured by the TUNEL assay, and apoptosis-related proteins BAX, caspase-3, and BCL-2 in the renal tissue were analyzed by western blot. The treatment with HSYA significantly decreased fasting blood glucose, CR, UN, and blood lipid profile, including triglyceride and total and low-density lipoprotein cholesterol, even though it did not change the rats’ body weights. The western blot results indicated that HSYA reversed the upregulation of BAX and caspase-3 and significantly increased BCL-2 in renal tissue. Moreover, the levels of TNF-α and the inflammatory products, including free fatty acids (FFA) and lactic dehydrogenase (LDH) in the HSYA group, were significantly decreased. For the oxidative stress marker, the superoxide dismutase (SOD) markedly increased in the HSYA treatment group, while the malondialdehyde (MDA) in the serum and kidney tissue evidently decreased. In conclusion, HSYA treatment preserved kidney function in diabetic nephropathy in the HFD- and STZ-induced rats. The potential mechanism of renal protective effect of HSYA might be through inhibiting oxidative stress, reducing inflammatory reaction, and attenuating renal cell apoptosis. Our studies present a promising use for Hydroxysafflor yellow A in the treatment of type 2 diabetes mellitus.

The role of vitamin D deficiency and elevated inflammatory biomarkers as risk factors for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus

2021 ◽  
Vol 19 (1) ◽  
pp. 1183-1192
Author(s):  
Ahmad El Askary ◽  
Amal F. Gharib ◽  
Mazen Almehmadi ◽  
Maha Mahfouz Bakhuraysah ◽  
Abdulaziz Ali Al Hajjiahmed ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Type 2 Diabetes ◽  
Vitamin D ◽  
Type 2 Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Vitamin D Deficiency ◽  
Diabetic Patients ◽  
Tnf Α

Abstract Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Albuminuria is the most sensitive marker for the early recognition of DN. Therefore, we aimed to study the risk factors of albuminuria as a marker of DN among diabetic patients. The study included 41 patients with type 2 diabetes mellitus (T2DM), 50 type 2 diabetic nephropathy (T2DN) patients with macroalbuminuria, 43 T2DN patients with microalbuminuria and 38 healthy controls. Logistic regression was used to detect the most significant risk factors for albuminuria. A high statistically significant difference was found between the groups regarding age, sex, body mass index (BMI), diabetes mellitus (DM) duration, glucose, glycated haemoglobin (HbA1c), creatinine, glomerular filtration rate (GFR), lipid profile, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), the albumin–creatinine ratio (ACR), vitamin D, total parathyroid hormone (PTH), urea, total calcium and chemerin (p < 0.001). It was found that the duration of DM, BMI, glucose, GFR, total cholesterol (TC), low-density lipoprotein (LDL), TNF-α, IL-6, CRP, ACR, vitamin D, PTH and chemerin are significant albuminuria risk factors in DN. Vitamin D deficiency and associated inflammatory mediators such as chemerin, TNF-α, IL-6 and CRP are the most essential risk factors for albuminuria in T2DM patients.

ADMA and oxidative stress may relate to the progression of renal disease: rationale and design of the VIVALDI study

2005 ◽  
Vol 10 (1_suppl) ◽  
pp. S97-S102 ◽  
Author(s):  
Rainer H Böger ◽  
Edzard Schwedhelm ◽  
Renke Maas ◽  
Sabine Quispe-Bravo ◽  
Cord Skamira
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Vascular Function ◽  
Angiotensin Receptor Blockers ◽  
Angiotensin Receptor ◽  
Endogenous Inhibitor ◽  
Receptor Blockers ◽  
Circulating Levels

The renin angiotensin system has been shown to be involved in the patho genesis of vascular and renal sequelae of diabetes mellitus. In type 2 diabetes mel litus, angiotensin receptor blockers have been shown to exert clinical benefit by reducing the progression of diabetic nephropathy. They also improve endothelium- mediated vascular function. The latter effect is partly due to the reduction of angiotensin II-associated oxidative stress. Moreover, small clinical studies have shown that treatment with angiotensin receptor blockers also reduces the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. In the VIVALDI trial, the ability of the angiotensin receptor blocker telmisartan to reduce the progression of diabetic nephropathy (associated with proteinuria) in com parison with valsartan in more than 800 patients with type 2 diabetes during 1 year of treatment is being studied. In order to gain more detailed insight into the poten tial pathomechanisms associated with this effect, further end-points have been defined. Among these are the circulating levels of ADMA and the urinary excretion rate of 8-iso-prostaglandin F2α (8-iso-PGF 2α). The former is an endogenous inhibitor of NO-mediated vascular function(s) and a prospectively determined marker of major cardiovascular events and mortality; the latter is a lipid peroxidation product resulting from the nonenzymatic peroxidation of arachidonic acid, which exerts detrimental vascular effects similar to those of thromboxane A2. Urinary 8-iso-PGF 2α has been shown in clinical studies to be an independent marker of cardiovascular disease. Highlighting the effects of telmisartan on ADMA and 8-iso-PGF levels in such a large cohort of diabetic patients will enhance our understanding of the roles of dys functional NO metabolism and redox mechanisms in the pathogenesis of end-organ damage and its prevention by pharmacotherapy with angiotensin receptor blockers.

scholarly journals Comparison Of The Effect Of Vitamin E And Rosmarinic Acid On Expression Of P65 NF-KB Subunit In Diabetes Rat

2020 ◽  
Vol 6 (2) ◽  
pp. 117
Author(s):  
Wahyu Prima ◽  
Nur Samsu ◽  
Husnul Khotimah
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Vitamin E ◽  
Rosmarinic Acid ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Significant Difference

One of the causes of diabetic nephropathy (ND) that have important role is the increase of free radicals due to high levels of glucose which causes oxidative stress. Oxidative stress activates Angiotensin II and the transcription factor of Nuclear Factor kappa B (NFKb). Prevention and slowing down of ND progression is by using antioxidants. The example of antioxidants are Vitamin E and Rosmarinic Acid (RA). Vitamin E is a conventional antioxidant while RA is a potent antioxidant that also has anti-inflammatory effects. This laboratory experimental study aimed to compare the effects of Vitamin E and RA on the expression of NFKb p-65 in glomelurus of type 2 diabetes rats. NFKb expression of p-65 of positive control increased significantly compared to negative controls (p <0.001), Vitamin E and RA were able to reduce NFKb expression compared to positive controls (p = 0.022 and p = 0.001). respectively there was no significant difference between NFKb expression in the Vitamin E group and Rosmarinic acid but RA decreased better than Vitamin E. It can be concluded that AR had a better effect compared to Vitamin E on the decrease in NFKb p-65 expression in glomelurus type 2 diabetes rats. Keyword: Diabetic nephropathy, Nuclear Factor kappa B (NF-Kb), Rosmarinic Acid, Vitamin E

scholarly journals The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes

2018 ◽  
Vol 29 (4) ◽  
pp. 1108-1127 ◽  
Author(s):  
Yaeni Kim ◽  
Ji Hee Lim ◽  
Min Young Kim ◽  
Eun Nim Kim ◽  
Hye Eun Yoon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Protein Kinase ◽  
Endothelial Dysfunction ◽  
High Glucose ◽  
Receptor Agonist ◽  
Intracellular Ca ◽  
Intracellular Pathways

Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor–α (PPARα) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase–β (CaMKKβ) and numbers of phosphorylated liver kinase B1 (LKB1)– and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKKβ, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, and PPARα expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose–treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKKβ/phosphorylated Ser431LKB1/phosphorylated Thr172AMPK/PPARα pathway and downstream signaling, thus decreasing high-glucose–induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPARα pathway, suggesting its efficacy for treating type 2 diabetes–associated DN.

scholarly journals Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation

2018 ◽  
Vol 19 (9) ◽  
pp. 2706 ◽  
Author(s):  
Cristina Sena ◽  
Maria Cipriano ◽  
Maria Botelho ◽  
Raquel Seiça
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Liver Function ◽  
Hepatic Steatosis ◽  
Lipoic Acid ◽  
High Fat Diet ◽  
Control Group ◽  
High Fat ◽  
Tnf Α

Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.

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