scholarly journals Administration of a substituted adamantyl urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto–Kakizaki rats

2008 ◽  
Vol 116 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Jeffrey J. Olearczyk ◽  
Jeffrey E. Quigley ◽  
Bradford C. Mitchell ◽  
Tatsuo Yamamoto ◽  
In-Hae Kim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Histological Evaluation ◽  
Kidney Cortex ◽  
Tubular Damage ◽  
Dodecanoic Acid ◽  
Monocyte Chemoattractant Protein 1 ◽  
Gk Rats

Hypertension and Type 2 diabetes are co-morbid diseases that lead to the development of nephropathy. sEH (soluble epoxide hydrolase) inhibitors are reported to provide protection from renal injury. We hypothesized that the sEH inhibitor AUDA [12-(3-adamantan-1-yl-ureido)-dodecanoic acid] protects the kidney from the development of nephropathy associated with hypertension and Type 2 diabetes. Hypertension was induced in spontaneously diabetic GK (Goto–Kakizaki) rats using AngII (angiotensin II) and a high-salt diet. Hypertensive GK rats were treated for 2 weeks with either AUDA or its vehicle added to drinking water. MAP (mean arterial pressure) increased from 118±2 mmHg to 182±20 and 187±6 mmHg for vehicle and AUDA-treated hypertensive GK rats respectively. AUDA treatment did not alter blood glucose. Hypertension in GK rats resulted in a 17-fold increase in urinary albumin excretion, which was decreased with AUDA treatment. Renal histological evaluation determined that AUDA treatment decreased glomerular and tubular damage. In addition, AUDA treatment attenuated macrophage infiltration and inhibited urinary excretion of MCP-1 (monocyte chemoattractant protein-1) and kidney cortex MCP-1 gene expression. Taken together, these results provide evidence that sEH inhibition with AUDA attenuates the progression of renal damage associated with hypertension and Type 2 diabetes.

Serum Soluble Epoxide Hydrolase Related Oxylipins and Depression in Patients With Type 2 Diabetes: An Exploratory Lipidomic Study

2021 ◽  
Vol 89 (9) ◽  
pp. S245-S246
Author(s):  
Natasha Z. Anita ◽  
Nubaira Forkan ◽  
Radia Kamal ◽  
Michelle M. Nguyen ◽  
Di Yu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase

Serum soluble epoxide hydrolase related oxylipins and major depression in patients with type 2 diabetes

2021 ◽  
Vol 126 ◽  
pp. 105149
Author(s):  
Natasha Z. Anita ◽  
Nubaira Forkan ◽  
Radia Kamal ◽  
Michelle M. Nguyen ◽  
Di Yu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Major Depression ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase

Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes

Diabetes ◽  
1999 ◽  
Vol 48 (4) ◽  
pp. 927-932 ◽  
Author(s):  
Y. Ihara ◽  
S. Toyokuni ◽  
K. Uchida ◽  
H. Odaka ◽  
T. Tanaka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Gk Rats

scholarly journals Renal Involvement in Children with Type 2 Diabetes Mellitus Onset: A Pilot Study

Children ◽  
2021 ◽  
Vol 8 (8) ◽  
pp. 627
Author(s):  
Pierluigi Marzuillo ◽  
Anna Di Sessa ◽  
Pier Luigi Palma ◽  
Giuseppina Rosaria Umano ◽  
Cesare Polito ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Renal Involvement ◽  
Kidney Injury ◽  
Fractional Excretion ◽  
Tubular Damage ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Type 2 Diabetes Mellitus (T2DM) is a main cause of chronic kidney disease (CKD) in adulthood. No studies have examined the occurrence of acute kidney injury (AKI)—that enhances the risk of later CKD—and renal tubular damage (RTD)—that can evolve to AKI—in children with onset of T2DM. We aimed to evaluate the prevalence and possible features of AKI and RTD in a prospectively enrolled population of children with onset of T2DM. We consecutively enrolled 10 children aged 12.9 ± 2.3 years with newly diagnosed T2DM. AKI was defined according to the KDIGO criteria. RTD was defined by abnormal urinary beta-2-microglobulin and/or tubular reabsorption of phosphate (TRP) < 85% and/or fractional excretion of Na > 2%. None of the patients developed AKI, whereas 3/10 developed RTD with high beta-2-microglobulin levels (range: 0.6–1.06 mg/L). One of these three patients also presented with reduced TRP levels (TRP = 70%). Proteinuria was observed in two out of three patients with RTD, while none of patients without RTD had proteinuria. Patients with RTD presented higher beta-2-microglobulin, acute creatinine/estimated basal creatinine ratio, and serum ketones levels compared with patients without RTD. In conclusion, in our pilot observation, we found that none of the 10 children with T2DM onset developed AKI, whereas three of them developed RTD.

scholarly journals Role of TLR4/MyD88/NF-κB signaling in heart and liver-related complications in a rat model of type 2 diabetes mellitus

2021 ◽  
Vol 49 (3) ◽  
pp. 030006052199759
Author(s):  
Jiajia Tian ◽  
Yanyan Zhao ◽  
Lingling Wang ◽  
Lin Li
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Signaling Pathway ◽  
Rat Model ◽  
Fasting Blood Glucose ◽  
Diabetic Rats ◽  
Primary Response ◽  
Monocyte Chemoattractant Protein 1

Aims To analyze expression of members of the Toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/nuclear factor (NF)-κB signaling pathway in the heart and liver in a rat model of type 2 diabetes mellitus (T2DM). Our overall goal was to understand the underlying pathophysiological mechanisms. Methods We measured fasting blood glucose (FBG) and insulin (FINS) in a rat model of T2DM. Expression of members of the TLR4/MyD88/NF-κB signaling pathway as well as downstream cytokines was investigated. Levels of mRNA and protein were assessed using quantitative real-time polymerase chain reaction and western blotting, respectively. Protein content of tissue homogenates was assessed using enzyme-linked immunosorbent assays. Results Diabetic rats had lower body weights, higher FBG, higher FINS, and higher intraperitoneal glucose tolerance than normal rats. In addition, biochemical indicators related to heart and liver function were elevated in diabetic rats compared with normal rats. TLR4 and MyD88 were involved in the occurrence of T2DM as well as T2DM-related heart and liver complications. TLR4 caused T2DM-related heart and liver complications through activation of NF-κB. Conclusions TLR4/MyD88/NF-κB signaling induces production of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, leading to the heart- and liver-related complications of T2DM.

scholarly journals Type 2 diabetes mellitus in the Goto-Kakizaki rat impairs microvascular function and contributes to premature skeletal muscle fatigue

2019 ◽  
Vol 126 (3) ◽  
pp. 626-637 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
Matthew T. Lewis ◽  
Jonathan D. Kasper ◽  
Paul D. Chantler ◽  
Robert W. Wiseman
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Type 2 Diabetes Mellitus ◽  
Structure Function ◽  
Vascular Structure ◽  
Gk Rats ◽  
The Impact

Despite extensive investigation into the impact of metabolic disease on vascular function and, by extension, tissue perfusion and organ function, interpreting results for specific risk factors can be complicated by the additional risks present in most models. To specifically determine the impact of type 2 diabetes without obesity on skeletal muscle microvascular structure/function and on active hyperemia with elevated metabolic demand, we used 17-wk-old Goto-Kakizaki (GK) rats to study microvascular function at multiple levels of resolution. Gracilis muscle arterioles demonstrated blunted dilation to acetylcholine (both ex vivo proximal and in situ distal arterioles) and elevated shear (distal arterioles only). All other alterations to reactivity appeared to reflect compromised endothelial function associated with increased thromboxane (Tx)A2 production and oxidant stress/inflammation rather than alterations to vascular smooth muscle function. Structural changes to the microcirculation of GK rats were confined to reduced microvessel density of ~12%, with no evidence for altered vascular wall mechanics. Active hyperemia with either field stimulation of in situ cremaster muscle or electrical stimulation via the sciatic nerve for in situ gastrocnemius muscle was blunted in GK rats, primarily because of blunted functional dilation of skeletal muscle arterioles. The blunted active hyperemia was associated with impaired oxygen uptake (V̇o2) across the muscle and accelerated muscle fatigue. Acute interventions to reduce oxidant stress (TEMPOL) and TxA2 action (SQ-29548) or production (dazmegrel) improved muscle perfusion, V̇o2, and muscle performance. These results suggest that type 2 diabetes mellitus in GK rats impairs skeletal muscle arteriolar function apparently early in the progression of the disease and potentially via an increased reactive oxygen species/inflammation-induced TxA2 production/action on network function as a major contributing mechanism. NEW & NOTEWORTHY The impact of type 2 diabetes mellitus on vascular structure/function remains an area lacking clarity. Using diabetic Goto-Kakizaki rats before the development of other risk factors, we determined alterations to vascular structure/function and skeletal muscle active hyperemia. Type 2 diabetes mellitus reduced arteriolar endothelium-dependent dilation associated with increased thromboxane A2 generation. Although modest microvascular rarefaction was evident, there were no other alterations to vascular structure/function. Skeletal muscle active hyperemia was blunted, although it improved after antioxidant or anti-thromboxane A2 treatment.

Abstract TP436: Dysfunctional Cerebral Neovascularization And Remodeling Patterns In Obese And Lean Models Of Type 2 Diabetes

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Roshini Prakash ◽  
Maribeth Johnson ◽  
Susan C Fagan ◽  
Adviye Ergul
Keyword(s):  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Structural Characteristics ◽  
Structural Parameters ◽  
Volume Density ◽  
3 Dimensional ◽  
Gk Rats ◽  
Dimensional Reconstruction ◽  
Branch Density

We previously reported intense pial cerebral collateralization and arteriogenesis in a mild and lean model of type 2 diabetes, Goto-Kakizaki (GK) rats. Further 3-dimensional fluroscein (FITC) imaging studies revealed regional differences in increased cerebral neovascularization which was associated with poor vessel wall maturity. Building upon these findings, the goals of this study were a) to compare and contrast this pathological neovascularization pattern in db/db mice and GK models of diabetes, and b) determine the effect of glycemic control on erratic cerebral neovascularization. Total vascular volume, density and surface area as well as structural parameters including microvessel/macrovessel ratio, non-FITC perfusing vessel abundance, penetrating arteriole (PA) branching density and diameter, and tortuosity were measured by 3 dimensional reconstruction of FITC stained vasculature using Z-stacked images obtained with confocal microscopy. Lean GK rats exhibited an increase in both micro and macrovessel density, non-perfusing vessel abundance, branch density, diameter and tortuosity. Glycemic control with metformin prevented these changes. Obese db/db mice, on the other hand, showed an increase in only microvascular density but this was not associated with an increase in non-FITC perfusing vessels. PA branch density was higher than controls but branch diameter was reduced. Diabetes also promoted astrogliosis. These results suggests that type 2 diabetes leads to cerebral neovascularization and remodeling but structural characteristics of newly formed vessels differ between lean and obese models that have mild or severe hyperglycemia, respectively. The prevention of dysfunctional cerebral neovascularization by early glucose control suggests that hyperglycemia is a mediator of this response. N=4-8 * p≤ 0.05, ** p≤ 0.005 *** 0.0005

scholarly journals Adenosine A2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ

2013 ◽  
Vol 304 (1) ◽  
pp. R23-R32 ◽  
Author(s):  
Mohammed A. Nayeem ◽  
Isha Pradhan ◽  
S. Jamal Mustafa ◽  
Christophe Morisseau ◽  
John R. Falck ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Induced Response ◽  
Dodecanoic Acid ◽  
Peroxisome Proliferator ◽  
Vascular Response ◽  
Cgs 21680 ◽  
Adenosine Receptor Agonist ◽  
Sch 58261 ◽  
Pparα Agonist

The interaction between adenosine and soluble epoxide hydrolase (sEH) in vascular response is not known. Therefore, we hypothesized that lack of sEH in mice enhances adenosine-induced relaxation through A2A adenosine receptors (AR) via CYP-epoxygenases and peroxisome proliferator-activated receptor γ (PPARγ). sEH−/− showed an increase in A2A AR, CYP2J, and PPARγ by 31%, 65%, and 36%, respectively, and a decrease in A1AR and PPARα (30% and 27%, respectively) vs. sEH+/+. 5′-N-ethylcarboxamidoadenosine (NECA, an adenosine receptor agonist), CGS 21680 (A2A AR-agonist), and GW 7647 (PPARα-agonist)-induced responses were tested with nitro-l-arginine methyl ester (l-NAME) (NO-inhibitor; 10−4 M), ZM-241385, SCH-58261 (A2A AR-antagonists; 10−6 M), 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an epoxyeicosatrienoic acid-antagonist; 10−5 M), 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA; 10 μM) or trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid ( t-AUCB, sEH-inhibitors; 10−5 M), and T0070907 (PPARγ-antagonist; 10−7 M). In sEH−/− mice, ACh response was not different from sEH+/+ ( P > 0.05), and l-NAME blocked ACh-responses in both sEH−/− and sEH+/+ mice ( P < 0.05). NECA (10−6 M)-induced relaxation was higher in sEH−/− (+12.94 ± 3.2%) vs. sEH+/+ mice (−5.35 ± 5.2%); however, it was blocked by ZM-241385 (−22.42 ± 1.9%) and SCH-58261(−30.04 ± 4.2%). CGS-21680 (10−6 M)-induced relaxation was higher in sEH−/− (+37.4 ± 5.4%) vs. sEH+/+ (+2.14 ± 2.8%). l-NAME (sEH−/−, +30.28 ± 4.8%, P > 0.05) did not block CGS-21680-induced response, whereas 14,15-EEZE (−7.1 ± 3.7%, P < 0.05) did. Also, AUDA and t-AUCB did not change CGS-21680-induced response in sEH−/− ( P > 0.05), but reversed in sEH+/+ (from +2.14 ± 2.8% to +45.33 ± 4.1%, and +63.37 ± 7.2, respectively). PPARα-agonist did not relax as CGS 21680 (−2.48 ± 1.1 vs. +37.4 ± 5.4%) in sEH−/−, and PPARγ-antagonist blocked (from +37.4 ± 5.4% to +9.40 ± 3.1) CGS 21680-induced relaxation in sEH−/−. Our data suggest that adenosine-induced relaxation in sEH−/− may depend on the upregulation of A2A AR, CYP2J, and PPARγ, and the downregulation of A1 AR and PPARα.

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