Valsartan slows the progression of diabetic nephropathy in db/db mice via a reduction in podocyte injury, and renal oxidative stress and inflammation

2014 ◽  
Vol 126 (10) ◽  
pp. 707-720 ◽  
Author(s):  
Guangyu Zhou ◽  
Alfred K. Cheung ◽  
Xia Liu ◽  
Yufeng Huang
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Podocyte Injury

Valsartan, given at a dose that reduces proteinuria, maximally slows the progression of the renal structural lesions resulting from Type 2 diabetes in db/db mice via protection of renal podocytes and a reduction in renal oxidative stress and inflammation.

scholarly journals Renal Podocyte Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Junghyun Kim ◽  
Eunjin Shon ◽  
Chan-Sik Kim ◽  
Jin Sook Kim
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Glycated Haemoglobin ◽  
Protective Effects ◽  
Podocyte Injury ◽  
Podocyte Loss ◽  
Renal Changes ◽  
Hypoglycemic Drug ◽  
Antioxidant Effects

Hyperglycemia promotes oxidative stress and hence generation of reactive oxygen species (ROS), which is known to play a crucial role in the pathogenesis of diabetic nephropathy. Metformin, an oral hypoglycemic drug, possesses antioxidant effects. The aim of this paper is to investigate the protective effects of metformin on the injury of renal podocytes in spontaneously diabetic Torii (SDT) rats, a new model for nonobese type 2 diabetes. Metformin (350 mg/kg/day) was given to SDT rats for 17 weeks. Blood glucose, glycated haemoglobin (HbA1c), and albuminuria were examined. Kidney histopathology, renal 8-hydroxydeoxyguanosine (8-OHdG) levels and apoptosis were examined. In 43-week-old SDT rats, severe hyperglycemia was developed, and albuminuria was markedly increased. Diabetes induced significant alterations in renal glomerular structure. In addition, urinary and renal 8-OHdG levels were highly increased, and podocyte loss was shown through application of the TUNEL and synaptopodin staining. However, treatment of SDT rats with metformin restored all these renal changes. Our data suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxidative injury.

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.

Lipotoxicity dysregulates the immunoproteasome in podocytes and kidneys in type 2 diabetes

2021 ◽  
Vol 320 (4) ◽  
pp. F548-F558
Author(s):  
Hyun Soon Lee ◽  
Ji Yeon Suh ◽  
Byeong-Choel Kang ◽  
Eugene Lee
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Fish Oil ◽  
Olive Oil ◽  
Renal Cortex ◽  
Diabetic Mice ◽  
Podocyte Injury ◽  
Type 2 Diabetic

In podocytes, PA rapidly induced immunoproteasome expression but ultimately decreased it, while OA and EPA restored the decreased immunoproteasome levels. In the renal cortex of type 2 diabetic mice, immunoproteasome expression was significantly decreased, whereas feeding of OA-rich olive oil or EPA-rich fish oil diets protected them against the reduced immunoproteasome expression and progression of diabetic nephropathy. Thus, lipotoxicity-induced podocyte injury with impaired immunoproteasome expression may be related to the pathogenesis of diabetic nephropathy.

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.

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.

scholarly journals Is Podocyte Injury Relevant in Diabetic Nephropathy?: Studies in Patients With Type 2 Diabetes

Diabetes ◽  
2003 ◽  
Vol 52 (4) ◽  
pp. 1031-1035 ◽  
Author(s):  
M. Dalla Vestra ◽  
A. Masiero ◽  
A. M. Roiter ◽  
A. Saller ◽  
G. Crepaldi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Podocyte Injury

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.

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