Role of haem oxygenase in the renoprotective effects of soluble epoxide hydrolase inhibition in diabetic spontaneously hypertensive rats

2013 ◽  
Vol 125 (7) ◽  
pp. 349-359 ◽  
Author(s):  
Ahmed A. Elmarakby ◽  
Jessica Faulkner ◽  
Chelsey Pye ◽  
Katelyn Rouch ◽  
Abdulmohsin Alhashim ◽  
...  
Keyword(s):  
Renal Injury ◽  
Renal Fibrosis ◽  
Spontaneously Hypertensive Rats ◽  
Epoxide Hydrolase ◽  
Transforming Growth Factor ◽  
Soluble Epoxide Hydrolase ◽  
Control Group ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Haem Oxygenase

We have shown previously that inhibition of sEH (soluble epoxide hydrolase) increased EETs (epoxyeicosatrienoic acids) levels and reduced renal injury in diabetic mice and these changes were associated with induction of HO (haem oxygenase)-1. The present study determines whether the inhibition of HO negates the renoprotective effect of sEH inhibition in diabetic SHR (spontaneously hypertensive rats). After 6 weeks of induction of diabetes with streptozotocin, SHR were divided into the following groups: untreated, treated with the sEH inhibitor t-AUCB {trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid}, treated with the HO inhibitor SnMP (stannous mesoporphyrin), and treated with both inhibitors for 4 more weeks; non-diabetic SHR served as a control group. Induction of diabetes significantly increased renal sEH expression and decreased the renal EETs/DHETEs (dihydroxyeicosatrienoic acid) ratio without affecting HO-1 activity or expression in SHR. Inhibition of sEH with t-AUCB increased the renal EETs/DHETEs ratio and HO-1 activity in diabetic SHR; however, it did not significantly alter systolic blood pressure. Treatment of diabetic SHR with t-AUCB significantly reduced the elevation in urinary albumin and nephrin excretion, whereas co-administration of the HO inhibitor SnMP with t-AUCB prevented these changes. Immunohistochemical analysis revealed elevations in renal fibrosis as indicated by increased renal TGF-β (transforming growth factor β) levels and fibronectin expression in diabetic SHR and these changes were reduced with sEH inhibition. Co-administration of SnMP with t-AUCB prevented its ability to reduce renal fibrosis in diabetic SHR. In addition, SnMP treatment also prevented t-AUCB-induced decreases in renal macrophage infiltration, IL-17 expression and MCP-1 levels in diabetic SHR. These findings suggest that HO-1 induction is involved in the protective effect of sEH inhibition against diabetic renal injury.

Abstract 309: Role of Hemeoxygenase in the Reno-Protective Effects of Soluble Epoxide Hydrolase Inhibition In Diabetic Spontaneously Hypertensive Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ahmed A Elmarakby ◽  
Jessica Faulkner ◽  
Chelsey Pye ◽  
Babak Baban ◽  
Katelyn Rouch ◽  
...  
Keyword(s):  
Protective Effect ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Spontaneously Hypertensive Rats ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Control Group ◽  
Protective Effects ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

We previously showed that inhibition of soluble epoxide hydrolase (sEH) increased epoxyeicosatrienoic acids (EETs) levels and reduced renal injury in diabetic mice and these changes were associated with induction of hemeoxygenase-1 (HO-1). The present study determines whether the inhibition of HO negates the reno-protective effect of sEH inhibition in diabetic spontaneously hypertensive rats as a model of diabetic nephropathy in which hypertension coexists with diabetes. After six weeks of induction of diabetes with streptozotocin, SHR were divided into the following groups: untreated, treated with the sEH inhibitor, trans -4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (AUCB), treated with the HO inhibitor, stannous mesoporphyrin (SnMP), and treated with both inhibitors for four more weeks; non diabetic SHR served as a control group. Although inhibition of sEH increased renal EETs/DHETEs ratio and HO-1 activity in diabetic SHR, it did not significantly alter blood pressure (plasma EETs/DHETEs ratio was 0.5± 0.1 in AUCB-treated vs. 0.1± 0.01 in untreated diabetic SHR, P<0.05). Treatment of diabetic SHR with AUCB reduced the elevation in urinary albumin and nephrin excretion (albuminuria was 6.5± 0.5 in AUCB-treated diabetic SHR vs. 9± 1.7 mg/day in untreated diabetic SHR and nephrinuria was 70±11 in AUCB-treated diabetic SHR vs. 111± 9 μg/day in untreated diabetic SHR, P<0.05) whereas co-administration of SnMP with AUCB prevented these changes (albuminuria was 10.6± 0.6 mg/day and nephrinuria was 91±11 μg/day). Immunohistochemical analysis revealed elevations in renal fibrosis and apoptosis as evidenced by increased renal TGF-β, fibronectin and annexin V expression in diabetic SHR and these changes were reduced with sEH inhibition. Co-administration of SnMP with AUCB prevented its ability to reduce renal fibrosis and apoptosis in diabetic SHR. In addition, SnMP treatment also prevented AUCB-induced decreases in renal macrophage infiltration and renal TGF-β, NFκB and MCP-1 levels in diabetic SHR. These data suggest that HO-1 induction is involved in the protective effect of sEH inhibition against diabetic renal injury.

scholarly journals Polymorphism in Soluble Epoxide Hydrolase and Blood Pressure in Spontaneously Hypertensive Rats

Hypertension ◽  
2002 ◽  
Vol 40 (4) ◽  
pp. 485-490 ◽  
Author(s):  
Myriam Fornage ◽  
Cruz A. Hinojos ◽  
Barbara W. Nurowska ◽  
Eric Boerwinkle ◽  
Bruce D. Hammock ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rats ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

scholarly journals System-based DNA microarray analyses of different gene expression profile in spontaneously hypertensive rats treated with Songling Xuemaikang Capsule reveals underlying causal mechanisms.

2019 ◽  
Author(s):  
Li-tao Liu ◽  
Cui-qi Yan ◽  
Qiao-xin Tang ◽  
Man-xi Zhao ◽  
Chuan-zhen Teng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Vascular Remodeling ◽  
Spontaneously Hypertensive Rats ◽  
Control Group ◽  
Causal Network ◽  
Ang Ii ◽  
Dosage Group ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Songling Xuemaikang Capsule

Abstract Background: Hypertension is considered the major risk factor for human health in the world. Songling Xuemaikang Capsule (SXC) is clinically used as a medicine for the prevention and treatment of cardiovascular and cerebrovascular diseases such as hypertension and hyperlipidemia. However, the underlying mechanisms have yet to be fully identified. Methods: Valsartan, as a positive control drug, high- and low-dose of SXC were orally administration with for 28 days to investigate the anti-hypertensive effect of SXC in spontaneously hypertensive rats (SHRs). The serum levels of aldosterone and Angiotensin II (Ang II) were detected. The gene expression profiling was performed in the thoracic aorta of SHRs using the Whole Rat Genome Oligo nucleotide Microarray. The integrated causal network analysis was performed to understand the mechanism of antihypertensive effect of SXC. Results: The results shown that the systolic and diastolic blood pressure were significant decreased in SXC low-dosage group and high-dosage group compared with the control group respectively. SXC low and high-dosage treatment decreased serum aldosterone levels significantly but increased serum Ang II compared with the control group respectively. Causal network analysis shown that treatment with SXC reversing the vascular remodeling process, inhibiting vascular inflammation and atherosclerosis, reversing endothelial cells dysfunction and likely reducing peripheral vascular resistance by down-regulated processes related to vascular remodeling, dyslipidemia, the complement system, leukocyte rolling, and endothelial dysfunction. In addition, SXC treatment may also activate fibrinolysis and regulate lipid and glucose metabolism. Conclusions: Those obtained data could help our understanding and potential utilization of SXC in the treatment or prevention of hypertension。

Effect of chlorothiazide on serial measurements of exchangeable sodium and blood pressure in spontaneously hypertensive rats

1985 ◽  
Vol 69 (5) ◽  
pp. 511-515 ◽  
Author(s):  
P. J. O. Manhem ◽  
S. A. Clark ◽  
W. B. Brown ◽  
G. D. Murray ◽  
J. I. S. Robertson
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Spontaneously Hypertensive Rats ◽  
Tap Water ◽  
Treated Group ◽  
Temporal Association ◽  
Control Group ◽  
Exchangeable Sodium ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

1. Chlorothiazide (100 mg/kg body weight) was given by gavage daily to spontaneously hypertensive rats for 4 weeks. Another group of spontaneously hypertensive rats was given only tap water and served as control. 2. Measurements of total exchangeable sodium, blood pressure and weight were performed for 2 weeks before and for 4 weeks during treatment. 3. Before treatment, exchangeable sodium, blood pressure and weight were similar in the two groups of rats. 4. Chlorothiazide significantly attenuated the blood pressure increase in spontaneously hypertensive rats, the effect being most marked during the first 2 1/2 weeks of treatment and less thereafter. 5. Rats in the chlorothiazide-treated group gained weight more slowly than did those of the control group. 6. Exchangeable sodium, expressed as mmol/kg body weight, did not differ significantly between the two groups at any stage. 7. When exchangeable sodium was expressed as mmol/rat, there was a more gradual rise in the chlorothiazide-treated animals, in accordance with their slower gain in weight. 8. There was no temporal association between the antihypertensive effect of chlorothiazide and changes in exchangeable sodium. 9. Thus whereas chlorothiazide treatment of spontaneously hypertensive rats slows the increase of both weight and exchangeable sodium, other mechanisms are apparently responsible for the antihypertensive action of the drug.

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