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Orally active epoxyeicosatrienoic acid analog attenuates kidney injury in hypertensive Dahl salt-sensitive rat.

ABSTRACT: Salt-sensitive hypertension leads to kidney injury. The Dahl salt-sensitive hypertensive rat (Dahl SS) is a model of salt-sensitive hypertension and progressive kidney injury. The current set of experimental studies evaluated the kidney protective potential of a novel epoxyeicosatrienoic acid analog (EET-B) in Dahl SS hypertension. Dahl SS rats receiving high-salt diet were treated with EET-B (10 mg/kg per day) or vehicle in drinking water for 14 days. Urine, plasma, and tissue samples were collected at the end of the treatment protocol to assess kidney injury, oxidative stress, inflammation, and endoplasmic reticulum stress. EET-B treatment in Dahl SS rats markedly reduced urinary albumin and nephrin excretion by 60% to 75% along with 30% to 60% reductions in glomerular injury, intratubular cast formation, and kidney fibrosis without affecting blood pressure. In Dahl SS rats, EET-B treatment further caused marked reduction in oxidative stress with 25% to 30% decrease in kidney malondialdehyde content along with 42% increase of nitrate/nitrite and a 40% reduction of 8-isoprostane. EET-B treatment reduced urinary monocyte chemoattractant protein-1 by 50% along with a 40% reduction in macrophage infiltration in the kidney. Treatment with EET-B markedly reduced renal endoplasmic reticulum stress in Dahl SS rats with reduction in the kidney mRNA expressions and immunoreactivity of glucose regulatory protein 78 and C/EBP homologous protein. In summary, these experimental findings reveal that EET-B provides kidney protection in Dahl SS rats by reducing oxidative stress, inflammation, and endoplasmic reticulum stress, and this protection was independent of reducing blood pressure.

SUBMITTER: Hye Khan MA

PROVIDER: S-EPMC3872985 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Orally active epoxyeicosatrienoic acid analog attenuates kidney injury in hypertensive Dahl salt-sensitive rat.

Hye Khan Md Abdul MA Neckár Jan J Manthati Vijay V Errabelli Ramu R Pavlov Tengis S TS Staruschenko Alexander A Falck John R JR Imig John D JD

Hypertension (Dallas, Tex. : 1979) 20130826 5

Salt-sensitive hypertension leads to kidney injury. The Dahl salt-sensitive hypertensive rat (Dahl SS) is a model of salt-sensitive hypertension and progressive kidney injury. The current set of experimental studies evaluated the kidney protective potential of a novel epoxyeicosatrienoic acid analog (EET-B) in Dahl SS hypertension. Dahl SS rats receiving high-salt diet were treated with EET-B (10 mg/kg per day) or vehicle in drinking water for 14 days. Urine, plasma, and tissue samples were coll ...[more]

PMID: 23980070

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Project description:Hypertensive cerebropathy is a pathological condition associated with cerebral edema and disruption of the blood-brain barrier. However, the molecular pathways leading to this condition remains obscure. We hypothesize that MMP-9 inhibition can help reducing blood pressure and endothelial disruption associated with hypertensive cerebropathy. Dahl salt-sensitive (Dahl/SS) and Lewis rats were fed with high-salt diet for 6 weeks and then treated without and with GM6001 (MMP inhibitor). Treatment of GM6001 (1.2 mg/kg body weight) was administered through intraperitoneal injections on alternate days for 4 weeks. GM6001 non-administered groups were given vehicle (0.9% NaCl in water) treatment as control. Blood pressure was measured by tail-cuff method. The brain tissues were analyzed for oxidative/nitrosative stress, vascular MMP-9 expression, and tight junction proteins (TJPs). GM6001 treatment significantly reduced mean blood pressure in Dahl/SS rats which was significantly higher in vehicle-treated Dahl/SS rats. MMP-9 expression and activity was also considerably reduced in GM6001-treated Dahl/SS rats, which was otherwise notably increased in vehicle-treated Dahl/SS rats. Similarly MMP-9 expression in cerebral vessels of GM6001-treated Dahl/SS rats was also alleviated, as devised by immunohistochemistry analysis. Oxidative/nitrosative stress was significantly higher in vehicle-treated Dahl/SS rats as determined by biochemical estimations of malondialdehyde, nitrite, reactive oxygen species, and glutathione levels. RT-PCR and immunohistochemistry analysis further confirmed considerable alterations of TJPs in hypertensive rats. Interestingly, GM6001 treatment significantly ameliorated oxidative/nitrosative stress and TJPs, which suggest restoration of vascular integrity in Dahl/SS rats. These findings determined that pharmacological inhibition of MMP-9 in hypertensive Dahl-SS rats attenuate high blood pressure and hypertension-associated cerebrovascular pathology.

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Orally active epoxyeicosatrienoic acid analog attenuates kidney injury in hypertensive Dahl salt-sensitive rat.

Publications

Orally active epoxyeicosatrienoic acid analog attenuates kidney injury in hypertensive Dahl salt-sensitive rat.

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