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Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor β1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat

Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv Israel, aerman{at}clalit.org.il

Semyon Veksler

Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv Israel

Uzi Gafter

Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv Israel

Geoffrey Boner

Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv Israel

Clara Wittenberg

Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv Israel

David Jonathan van Dijk

Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv Israel

Introduction

Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor β1 (TGF-β1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-β1 in diabetic rats.

Materials and methods

Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days.

Results

Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-β₁ increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-β1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558).

Conclusions

Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-β1.

Key Words: renin-angiotensin system • TGF-β1 • ACE-I • ARB • diabetes mellitus • proteinuria

Journal of Renin-Angiotensin-Aldosterone System, Vol. 5, No. 3, 146-151 (2004)
DOI: 10.3317/jraas.2004.032


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