Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor beta 1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat.
BACKGROUND
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.


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-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).


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-beta 1.
Erman
Arie
A
Department of Nephrology and Hypertension, Rabin Medical Center, Petah Tikva 49100, Israel. aerman@clalit.org.il
Veksler
Semyon
S
Gafter
Uzi
U
Boner
Geoffrey
G
Wittenberg
Clara
C
van Dijk
David Jonathan
DJ
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000473:pathology / Q000652:urine; D004357:Drug Synergism; D004656:Enalapril / Q000494:pharmacology; D006984:Hypertrophy; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D011507:Proteinuria / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000097:blood*; D053773:Transforming Growth Factor beta1
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004656:Enalapril; D019808:Losartan