A thromboxane A2 synthetase inhibitor retards hypertensive rat diabetic nephropathy

Masumura, Hidemi; Kunitada, Satoshi; Irie, Kiyoshi; Ashida, Shinji; Abe, Youichi

doi:10.1016/0014-2999(92)90667-s

Cited by 17 publications

(12 citation statements)

References 33 publications

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“…One of important factors of ‘hyperfiltration’ [14]has been considered to be abnormal production and metabolism of prostaglandins (PGs) [15, 16]in the kidneys. Various prostaglandins produced in the kidneys, PGE 2 , PGI 2 and thromboxane A 2 (TXA 2 ), are potent vasoactive substances.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that the ratio of urinary 6-keto-PGF1 1α (a stable metabolite of PGI 2 ) and TXB 2 (a stable metabolite of TXA 2 ) in diabetic patients is smaller than that in healthy persons [17]. Increased production of TXA 2 , which has a potent activity accelerating platelet aggregation and vasoconstriction action, in the kidneys causes decreased renal blood flow due to increased renal vascular resistance and hyperaggregation in the glomeruli, and highly relates to development and progression of diabetic nephropathy [15, 16]. …”

Section: Discussionmentioning

confidence: 99%

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Alteration of Endothelin-1 Concentration in STZ-Induced Diabetic Rat Nephropathy

et al. 2001

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Background: Recently, an endothelin (ET-1) with a potent vasoconstrictive activity and stimulative activity of vascular muscular cell growth was discovered and blood ET-1 levels were higher in diabetic patients than in healthy subjects, suggesting that high ET-1 levels assist development and progression of diabetic microangiography. Methods: We examined renal function, and serum and tissue ET-1 levels in streptozotocin (STZ)-induced diabetic rats treated with a prostaglandin (PG) I₂ derivative to investigate the effect of PGI₂ in diabetic vascular disturbance. Results: Renal weight, urinary albumin, urinary N-acetyl-β,D-glucosaminidase (NAG) and serum ET-1 levels increased in STZ-induced diabetic rats, and a tendency to increase in renal tissue ET-1 levels was observed. Furthermore, electron-microscopic findings in the kidneys showed mesangial cell proliferation and mesangial matrix expansion which might be caused by diabetic nephropathy. The PGI₂ derivative reduced urinary albumin and NAG levels in STZ-induced rats. It was considered, therefore, that the PGI₂ derivative is effective in diabetic nephropathy. As the PGI₂ derivative also reduced renal tissue ET-1 levels, improvement of diabetic nephropathy partially was considered to result from the reduction of renal tissue ET-1 levels. Conclusion: In STZ-induced rats, increased serum ET-1 levels and a tendency to increase in renal tissue ET-1 levels were associated with increases in urinary albumin and NAG levels, and these levels were decreased by a PGI₂ derivative. These findings suggested that increased ET-1 concentrations assist development and progression of diabetic nephropathy, especially diabetic microangiopathy, and the PGI₂ derivative may be effective for inhibition of diabetic microangiopathy mediated by reduction of ET-1 concentrations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alteration of Endothelin-1 Concentration in STZ-Induced Diabetic Rat Nephropathy

et al. 2001

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“…Additionally, it has been indicated that the increased production of thromboxane A 2 in kidneys may be another factor to aggravate the symptoms of diabetic nephropathy, due to inducing platelet aggregation in glomeruli [4, 5]. PGI 2 is mainly produced in vascular endothelial cells and has a very strong effect to inhibit platelet aggregation, which contradicts the effects of thromboxane A 2 .…”

Section: Introductionmentioning

confidence: 97%

Effect of Long-Term Administration of Prostaglandin I<sub>2</sub> in Incipient Diabetic Nephropathy

Owada

Suda²,

Hata³

2002

Nephron

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Background/Aims: Diabetic nephropathy is one of the primary diseases of refractory renal failure and heads the list of patients undergoing dialysis. Therefore, it is very important to get treatment in incipient nephropathy. Methods: Twenty-seven patients in incipient diabetic nephropathy of type 2 diabetes mellitus who showed signs of microalbuminuria were randomly, but not blindly, assigned to two groups, either the beraprost sodium (PGI₂) group or the control group, and effects of the preparation on urinary albumin excretion or other parameters were examined for 24 months. Results: Urinary albumin excretion was significantly decreased after 18 months in beraprost sodium group; however, there was no change in the control group. Difference was observed between the two groups after month 12; however, it was not significant (p = 0.0673 at month 24). Three factors that affect urinary albumin excretion, e.g. blood pressure, blood sugar and protein intake, were almost constant during the study period. The level of creatinine clearance was significantly decreased in beraprost sodium group after 24 months as compared with the control group. Conclusion: In this study, we found that the long-term 24-month administration of PGI₂ preparation, beraprost sodium, decreased albuminuria in patients of incipient diabetic nephropathy. The possible mechanisms are that the PGI₂ may have alleviated constriction effect of angiotensin II on efferent glomerular arteriole and attenuated glomerular hyperfiltration, and inhibited growth of mesangial cells by platelet-derived growth factor as well.

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“…Diabetic patients treated with TX synthase inhibitors have decreased urinary protein and albumin levels [67][68][69]. Likewise, inhibition of TX synthase preserved renal blood flow and slowed the progression renal damage in diabetic rats [62,67,69]. Rofecoxib, a COX-2 inhibitor, decreases vascular and glomerular damage when administered to obese Zucker rats [29].…”

Section: Eicosanoids As a Therapeutic Target For Renal Damage In Cardmentioning

confidence: 99%

Eicosanoids and renal damage in cardiometabolic syndrome

Imig

2008

Expert Opinion on Drug Metabolism & Toxicology

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Obesity, hypertension and type 2 diabetes are major contributing factors to the increase in the number of patients that have chronic kidney disease. The clustering of visceral obesity and cardiovascular risk factors has been designated metabolic syndrome or cardiometabolic syndrome. Cardiometabolic syndrome is associated with a complex systemic inflammatory state that has been implicated in medically important complications including endothelial dysfunction. Inflammation, endothelial dysfunction, and insulin resistance are interrelated and have reciprocal relationships that link cardiovascular and metabolic diseases. Ultimately, cardiometabolic syndrome increases the risk for cardiovascular events and end organ damage. Although the number of patients with cardiometabolic syndrome is escalating, therapeutic approaches have not been developed that provide protection to the kidney. Eicosanoids are altered in cardiometabolic syndrome and contribute the progression of renal injury. The anti-hypertensive and anti-inflammatory actions of epoxides and soluble epoxide hydrolase inhibitors make these attractive eicosanoid therapeutic targets for chronic kidney disease in patients with cardiometabolic syndrome. Keywordskidney; epoxyeicosatrienoic acids; epoxide hydrolase; obesity; cytokines; inflammation Cardiometabolic SyndromeIn recent years, the number of obese people in the world is growing rapidly and has reached epidemic status. Obesity is the central phenotype in metabolic syndrome, also known as cardiometabolic syndrome that clusters with other cardiovascular risk factors. These other cardiovascular risk factors include hypertension, type 2 diabetes, insulin resistance, low high-density lipoproteins (HDL) cholesterol, elevated triglycerides, microalbuminuria, and atherosclerosis [1,2,3] (Figure 1). The Adult treatment Panel II of the National Cholesterol Education Program has defined metabolic syndrome as any three of the following five traits: visceral obesity, hypertension, hypertriglyceridemia, low HDL cholesterol, and impaired fasting glucose [4]. Although obesity is the phenotypic hallmark of cardiometabolic syndrome, the other risk factors that manifest in individuals varies greatly. Blood pressure elevation in obese individuals is closely related to weight gain; however, not all obese individuals become hypertensive [5][6][7][8]. The relationship between obesity and hypertension is well established but the exact consequences to end organ damage remains unknown. Interestingly, hypertension and diabetes account for seventy percent of patients with end stage renal disease (ESRD) and the number of patients with ESRD will double in this decade [9,10]. One of the main reasons for the doubling in ESRD patients is the increase in obesity related type 2 diabetes and its co-existence with hypertension.

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A thromboxane A2 synthetase inhibitor retards hypertensive rat diabetic nephropathy

Cited by 17 publications

References 33 publications

Alteration of Endothelin-1 Concentration in STZ-Induced Diabetic Rat Nephropathy

Alteration of Endothelin-1 Concentration in STZ-Induced Diabetic Rat Nephropathy

Effect of Long-Term Administration of Prostaglandin I<sub>2</sub> in Incipient Diabetic Nephropathy

Eicosanoids and renal damage in cardiometabolic syndrome

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