The Angiotensin Type 1 Receptor Antagonist, Eprosartan, Attenuates the Progression of Renal Disease in Spontaneously Hypertensive Stroke-Prone Rats with Accelerated Hypertension

Abstract

The effects of the angiotensin type 1 (AT 1 ) receptor antagonist, eprosartan, were studied in a model of severe, chronic hypertension. Treatment of male spontaneously hypertensive stroke prone rats (SHR-SP) fed a high-fat, high-salt diet with eprosartan (60 mg/kg/day i.p.) for 12 weeks resulted in a lowering of blood pressure (250 Ϯ 9 versus 284 Ϯ 8 mm Hg), renal expression of transforming growth factor-␤ mRNA (1.5 Ϯ 0.2 versus 5.4 Ϯ 1.4) and the matrix components: plasminogen activator inhibitor-1 (5.2 Ϯ 1.4 versus 31.4 Ϯ 10.7), fibronectin (2.2 Ϯ 0.6 versus 8.2 Ϯ 2.2), collagen I-␣1 (5.6 Ϯ 2.0 versus 23.8 Ϯ 7.3), and collagen III (2.7 Ϯ 0.9 versus 7.6 Ϯ 2.1). Data were corrected for rpL32 mRNA expression and expressed relative to Wistar Kyoto (WKY) rats [ϭ1.0]. Expression of fibronectin protein was also lowered by eprosartan (0.8 Ϯ 0.1 versus 1.9 Ϯ 0.5), relative to WKY rats. Eprosartan provided significant renoprotection to SHR-SP rats as measured by decreased proteinuria (22 Ϯ 2 versus 127 Ϯ 13 mg/day) and histological evidence of active renal damage (5 Ϯ 2 versus 195 Ϯ 6) and renal fibrosis (5.9 Ϯ 0.7 versus 16.4 Ϯ 1.9) in vehicle-versus eprosartantreated rats, respectively. Our results demonstrated that AT 1 receptor blockade with eprosartan can reduce blood pressure and preserve renal structure and function in this model of severe, chronic hypertension. These effects were accompanied by a decreased renal expression of transforming growth factor-␤1, plasminogen activator inhibitor-1, and several other extracellular matrix proteins compared with vehicle-treated SHR-SP.The renin-angiotensin system is a major regulator of blood pressure within the body, through the maintenance of vascular tone and sodium homeostasis. The renin-angiotensin system has, however, also been implicated in a number of diseases, characterized by remodeling and fibrosis, including forms of progressive renal disease. The generation of angiotensin II can lead to organ damage through both mitogenic activity and profibrotic remodeling. Eprosartan is a potent (K i ϭ 1.4 nM) angiotensin II receptor antagonist selective for the AT 1 subtype. AT 1 receptor antagonists have been shown to attenuate the effects of exogenous angiotensin II (Wang et al., 1997) and to be renoprotective in the partial nephrectomy model of renal failure (Gandhi et al., 1999), as measured by its ability to attenuate the hypertension, proteinuria, and up-regulation in the expression of several profibrotic genes associated with this model (Wong et al., 2000). TGF-␤ gene expression has been shown to be upregulated in a number of animal models of fibrotic disease, including renal disease (Border and Noble, 1998) and can be induced by several different vasoactive mitogens, including angiotensin II (Klahr and Morrissey, 2000). This profibrotic cytokine mediates the up-regulation of several extracellular matrix component genes, including fibronectin and collagen, leading to increased synthesis of the extracellular matrix (Ignotz and Massague, 1986). Furthermore, TGF...

Inhibition of Rho-kinase attenuates nephrosclerosis and improves survival in salt-loaded spontaneously hypertensive stroke-prone rats

“…Oxidative stress leads to the activation of transcription factors such as nuclear factor kappa B, which in turn activate genes that trigger inflammation, including ICAM-1 [37]. Because fasudil inhibits the generation of reactive oxygen species [10], the inhibition of Rho-kinase might decrease the gene expression of ICAM-1 via the inhibition of ROS. In the present study, high-dose fasudil treatment significantly reduced mRNA expressions of ICAM-1 and p40phox and p47phox in association with the decrease in macrophage/ monocyte infiltration.…”

“…SHR-SP were used as a model of severe hypertension in this study because of the presence of extensive end-organ damage, including nephrosclerosis [10]. The rats were fed a low-salt diet (0.12% NaCl) during a 2-week acclimatization period.…”

Anti-Inflammatory Effects of AT1 Receptor Blockade Provide End-Organ Protection in Stroke-Prone Rats Independently from Blood Pressure Fall

“…at ASPET Journals on May 9, 2018 jpet.aspetjournals.org necessary for renal protection by other drugs in the same animal model (Barone et al, 1996;Abrahamsen et al, 2002). Similarly, clinical studies indicated that ARBs improve vascular function independently of the blood pressure-lowering effect (Klingbeil et al, 2002;Lewis, 2002;Viberti et al, 2002).…”

Host genetics and diet composition interact to modulate gut microbiota and predisposition to metabolic syndrome in spontaneously hypertensive stroke‐prone rats

“…The animals were fed either chow (13% fat, 62% carbohydrate, 25% protein, 3.41 kcal/g) or HFDs (33% fat, 53% carbohydrate, 14% protein, 4.4 kcal/g) for 12 wk, following our previously published methods (31). We and others have previously reported that HFD (30-33% energy from fat) promotes the development of risk factors of metabolic syndrome such as hypertension, renal damage, and stroke in SHRSP rats (31,(51)(52)(53)(54). Because 33% dietary fat more closely resembles the recommended calories from dietary fat for humans (55), this fat concentration was selected for the current study.…”