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 Materials and Methods Experimental Design. Male SHR-SP rats, progeny from the strain developed b