Effects of tight blood pressure control on glomerular hypertrophy in a model of genetic hypertension and experimental diabetes mellitus Roberto Bleuel Amazonas, José B. Lopes de Faria ⁎ Laboratory of Renal Pathophysiology, Nephrology Unit, State University of Campinas (UNICAMP), Campinas, SP, Brazil Received 30 March 2006; accepted 6 July 2006 Abstract The aim of this study was to evaluate the effect of prevention of hypertension on glomerular hypertrophy, renal cell replication and accumulation of glomerular fibronectin in a model of genetic hypertension and experimental diabetes. Four-week-old streptozotocin induced spontaneously hypertensive rats (SHR) were randomized for no treatment, or for treatment with captopril, losartan or triple therapy (hydrochlorothiazide, reserpine and hydralazine) for 20 days. Increase in systolic blood pressure was equally prevented by captopril (118 ± 15 mmHg), losartan (111 ± 9) and triple therapy (112 ± 14, p b 0.0001). Glomerular size was higher ( p b 0.005) in diabetic SHR (27,300 ± 2130 μm 2 ) compared with non-diabetic SHR (23,800 ± 307). The antihypertensive therapy with captopril (23,900 ± 175), losartan (23,800 ± 120), and triple therapy (23,400 ± 210) prevented the glomerular enlargement in diabetic SHR. Glomerular expression of fibronectin was increased in diabetic SHR (7.61 ± 1.22 densitometric unit) as compared to the controls (2.27 ± 2.15, p b 0.0001), and was decreased ( p b 0.0001 vs diabetic SHR) with captopril (2.49 ± 1.42), losartan (1.57 ± 1.1) and triple therapy (2.04 ± 1.42). The number of replicating glomerular cell significantly decreased in diabetic SHR and it was restored by all three antihypertensive regimes. The glomerular expression of p27 Kip1 was increased in diabetic SHR but it was not modified by antihypertensive treatment. Strict blood pressure control, in diabetic SHR independently of the class of antihypertensive agent, restores glomerular hypertrophy and renal cellular replication, and prevents the increment in glomerular fibronectin. © 2006 Elsevier Inc. All rights reserved. Keywords: Angiotensin antagonist; Angiotensin-converting enzyme inhibitor; Cell hypertrophy; Cell replication; Diabetes mellitus; Diabetic nephropathy; Fibronectin; Hypertension Introduction Glomerular enlargement is an early abnormality observed both in humans (Osterby and Gundersen, 1975) and in animal models of diabetic renal disease (Wolf and Ziyadeh, 1999). The mechanisms underlying the development of diabetic glomerular hypertrophy have not been fully established, but involve the accumulation of extracellular matrix proteins and the hypertro- phy of growth-arrested glomerular cells (Mason and Wahab, 2003; Shankland and Wolf, 2000). In mesangial cells these abnormalities seem to be mediated by an elevation in the expression of cyclin-dependent kinase (Cdk) inhibitors such as p27 Kip1 and p21 Cip1 (Al-Douahji et al., 1999; Wolf et al., 1997; Wolf et al., 1998). It has been shown that the administration of an ACE inhibitor to diabetic Bbdp rats reduces renal hypertrophy and p27 Kip1 expression (Wolf et al., 1999). The effects of hyperglycemia on cell-cycle inhibitors, cell hypertrophy and extracellular matrix deposition are mainly mediated by trans- forming growth factor β (TGF-β), an antiproliferative and hypertrophic cytokine (Sharma and Ziyadeh, 1994; Polyak et al., 1994; Monkawa et al., 2002). The use of spontaneously hypertensive rats (SHR), widely utilized as an animal model of human essential hypertension (Okamoto et al., 1966), rendered diabetic with streptozotocin has significantly contributed to the understanding of the mechanism of interaction between genetic hypertension and diabetes in the development and progression of renal disease (Cooper et al., 1988b). Several years ago, it was shown that the severity of renal lesions in diabetic SHR is much more pronounced than in their Life Sciences 79 (2006) 2135 – 2143 www.elsevier.com/locate/lifescie ⁎ Corresponding author. Division of Nephrology, Faculty of Medical Sciences, State University of Campinas, SP, Brazil. Tel.: +55 19 37887499; fax: +55 19 37887366. E-mail address: jblfaria@fcm.unicamp.br (J.B. Lopes de Faria). 0024-3205/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2006.07.008