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. 2013 Nov;62(5):905-13.
doi: 10.1161/HYPERTENSIONAHA.113.01949. Epub 2013 Aug 26.

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

Md Abdul Hye Khan  1 , Jan Neckár, Vijay Manthati, Ramu Errabelli, Tengis S Pavlov, Alexander Staruschenko, John R Falck, John D Imig
Affiliations

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

Md Abdul Hye Khan et al. Hypertension. 2013 Nov.

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.

Keywords: arachidonate epoxygenase; glomerular necrosis; hypertension; inflammation; oxidative stress.

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Figures

Figure 1
Figure 1
Fig 1A–B. (A) Structure of EET-B. (B) Effect of 14,15-EEZE on EET-B induced relaxation in mesenteric resistance arteries. Values are mean± S.E.M., *p< 0.05. vs. EET-B alone.
Figure 2
Figure 2
Fig 2A–C. (A) Urinary albumin-creatinine ratio, (B) kidney cortical and medullary cast area in different experimental groups. (C) Representative photomicrographs of Periodic acid-Schiff (PAS) staining (200x) depicting tubular cast formation (black arrows) in the kidney cortical and medullary sections of rats from different experimental groups.*p<0.05 vs. SSBN13rats treated with vehicle; #p<0.05 vs. vehicle treated Dahl SS rats. Data expressed as mean ± SEM, n=6–7.
Figure 3
Figure 3
Fig 3A–C. (A) Urinary excretion of nephrin, (B) representative photomicrographs of Periodic Acid-Schiff (PAS) staining (200x) depicting glomerular injury with mesangial expansion (yellow arrows) and other changes related to glomerular sclerosis in different experimental groups. (C) Semi-quantitative scoring of glomerular injury in rats from different experimental groups. *p<0.05 vs. SSBN13 rats treated with vehicle; #p<0.05 vs. vehicle treated Dahl SS rats. Data expressed as mean ± SEM, n=6–7.
Figure 4
Figure 4
Fig 4A–D. Urinary excretion of monocyte chemoattractant protein-1 (MCP-1) (A), mean ED-1 or CD68 positive macrophage/monocyte counts in the kidney cortex (B) and medulla (C) of rats from different experimental groups. Representative photomicrographs of immunohistochemical staining depicting ED-1 or CD68 positive macrophage/monocyte (yellow arrows) in the kidney of rat from different experimental groups (D). *p<0.05 vs. SSBN13 rats treated with vehicle; #p<0.05 vs. vehicle treated Dahl SS rats. Data expressed as mean ± SEM, n=6–7.
Figure 5
Figure 5
Fig 5A–C. Representative photomicrographs of Masson’s-Trichrome staining of kidney cortical (A) and medullary (B) sections depicting fibrosis (yellow arrows) along with the calculated fibrotic area (%) in the renal cortical and medullary sections of rats from different experimental groups (C). *p<0.05 vs. SSBN13 rats treated with vehicle; #p<0.05 vs. vehicle treated Dahl SS rats. Data expressed as mean ± SEM, n=6–7.
Figure 6
Figure 6
Fig 6A–D. Renal cortical (A) and medullary (B) contents of malondialdehyde (MDA) in rats of different experimental groups. Urinary excretion of 8-isoprostane (C) and nitrate/nitrite (D) in rats from different experimental groups. *p<0.05 vs. SSBN13 rats treated with vehicle; #p<0.05 vs. vehicle treated Dahl SS rats. Data expressed as mean ± SEM, n=6–7.
Figure 7
Figure 7
Fig 7A–C. Renal mRNA expression of endoplasmic reticulum stress markers glucose regulatory protein 78 or GRP78 (A) and C/EBP homologous protein or CHOP (B) in the kidney of rats from different experimental groups. Representative photomicrographs of immunohistochemical staining showing the expression and localization (black arrows) of GRP78 and CHOP in the kidney of rats from different experimental groups (C). *p<0.05 vs. SSBN13 rats treated with vehicle; #p<0.05 vs. vehicle treated Dahl SS rats. Data expressed as mean ± SEM, n=6–7.
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