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 GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e108587 ◽  
Author(s):  
Pawel P. Wolkow ◽  
Wladyslaw Kosiniak-Kamysz ◽  
Grzegorz Osmenda ◽  
Grzegorz Wilk ◽  
Beata Bujak-Gizycka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Endothelial Dysfunction ◽  
Gene Polymorphisms ◽  
Gtp Cyclohydrolase I ◽  
And Oxidative Stress ◽  
I Gene

Chronic consumption of an inositol-enriched beverage ameliorates endothelial dysfunction and oxidative stress in type 2 diabetes

2015 ◽  
Vol 18 ◽  
pp. 598-607 ◽  
Author(s):  
Antonio Hernández-Mijares ◽  
Celia Bañuls ◽  
Susana Rovira-Llopis ◽  
Ángeles Álvarez ◽  
Samuel Orden ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
And Oxidative Stress

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.

SO021EFFECTS OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITOR, CANAGLIFLOZIN ON GLOMERULAR HYPERFILTRATION AND OXIDATIVE STRESS IN MICE WITH TYPE 2 DIABETES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Megumi Kondo ◽  
KENGO KIDOKORO ◽  
Yoshihisa Wada ◽  
Atsuyuki Tokuyama ◽  
Hiroyuki Kadoya ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Kidney Disease ◽  
High Glucose ◽  
Glomerular Hyperfiltration ◽  
No Production ◽  
Sodium Glucose Cotransporter ◽  
Type 2 Diabetic ◽  
Urinary Space

Abstract Background and Aims In most developed countries, diabetic kidney disease (DKD) is the most common cause of chronic kidney disease, which can lead to end-stage renal disease. In recent clinical trials, sodium–glucose cotransporter 2 inhibitors (SGLT2is) slowed the progression of kidney disease as compared with a placebo in patients with type 2 diabetes. One of the main mechanisms of the renoprotective effects of SCLT2is in DKD is considered the ability of these inhibitors to improve glomerular hyperfiltration. We previously demonstrated that the adenosine/adenosine A1 receptor pathway played a pivotal role in the tubuloglomerular feedback(TGF) system in a type 1 diabetic model, Akita mice (Circulation, 2019). We also reported that increased oxidative stress was involved in the pathogenesis of diabetic vascular complications. Uncoupling of endothelial nitric oxide (NO) synthase (eNOS) via oxidation of tetrahydrobiopterin (BH4), a cofactor required for NO production, played a major role in generation of oxidative stress (AJPRP, 2005; JASN, 2013). In the present study, we explored the renal protective effects of SGLT2 inhibition, with a focus on glomerular hemodynamics and glomerular oxidative stress. Method This study used type 2 diabetic db/db mice and db/m+ mice as a control (male, 8wk old). We developed a novel method to measure the glomerular filtration rate of single nephrons (SNGFRs) in mice using multiphoton laser microscopy. In the first experiment, we measured the SNGFRs in 12 wk-old db/db and db/m+ mice to confirm glomerular hyperfiltration. Next, we evaluated the SNGFRs change before and after the administration of a single dose of canagliflozin (CANA) (10 mg/kg). The SNGFRs, glomerular permeability of macromolecules, glomerular reactive oxygen species (ROS) and NO production, and tetrahydrobiopterin (BH4) level in serum and kidney were evaluated after the CANA treatment for 8 wk. Finally, human glomerular endothelial cells (hGECs) were exposed to normal glucose (5 mmol/L), high glucose (30 mmol/L of D-glucose), or a hyperosmotic control (5 mmol/L of D-glucose plus 25 mmol/L of L-glucose) in the presence or absence of CANA (10 μmol/L). Results The CANA treatment ameliorated glomerular hyperfiltration in the db/db mice. In the db/db mice, glomerulus ROS production increased, and NO production decreased as compared with the levels in the control mice. CANA improved the imbalance between ROS and NO production. The serum and kidney concentrations of BH4 declined in the non-treated db/db mice, whereas the CANA treatment preserved the BH4 level. Leakage of 70-kD FITC-labeled albumin into the urinary space was observed in the db/db mice. The CANA treatment reduced the amount of FITC-labeled albumin in the urinary space of the db/db mice. The CANA treatment also alleviated vascular endothelial damage in glomeruli. BH4 levels decreased in the hGECs exposed to high glucose. CANA did not improved BH4 level in the hGECs exposed to high glucose. Conclusion SGLT2i ameliorated glomerular hyperfiltration, preserving BH4 levels and improving the glomerular ROS/NO imbalance in type 2 diabetic mice.

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