Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor β1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat
- 1 September 2004
- journal article
- Published by SAGE Publications in Journal of the Renin-Angiotensin-Aldosterone System
- Vol. 5 (3), 146-151
- https://doi.org/10.3317/jraas.2004.032
Abstract
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 beta 1 (TGF-beta 1) 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-beta 1 in diabetic rats. 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. Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-beta1 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-beta 1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558). 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-beta 1.Keywords
This publication has 30 references indexed in Scilit:
- Effect of enalapril and losartan on the events that precede diabetic nephropathy in ratsDiabetes/Metabolism Research and Reviews, 2002
- Add-on angiotensin receptor blockade with maximized ACE inhibitionKidney International, 2001
- Role of angiotensin II in diabetic nephropathyKidney International, 2000
- Dosing angiotensin II blockers—beyond blood pressureNephrology Dialysis Transplantation, 1999
- Captopril-induced reduction of serum levels of transforming growth Factor-β1 correlates with long-term renoprotection in insulin-dependent diabetic patientsAmerican Journal of Kidney Diseases, 1999
- ACE inhibition reduces proteinuria, glomerular lesions and extracellular matrix production in a normotensive rat model of immune complex nephritisKidney International, 1995
- Increased serum angiotensin converting enzyme activity in type T insulin—dependent diabetes mellitus: its relation to metabolic control and diabetic complicationsEuropean Journal of Clinical Investigation, 1994
- Angiotensin converting enzyme activity in the serum, lung and kidney of diabetic ratsEuropean Journal of Clinical Investigation, 1993
- Inhibition of angiotensin converting enzyme by ramipril in serum and tissue of manJournal Of Hypertension, 1991
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976