title: 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.
abstract: 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.
authors.affiliation: Department of Nephrology and Hypertension, Rabin Medical Center, Petah Tikva 49100, Israel. aerman@clalit.org.il
authors.forename: Arie
authors.initials: A
authors.lastname: Erman
authors.forename: Semyon
authors.initials: S
authors.lastname: Veksler
authors.forename: Uzi
authors.initials: U
authors.lastname: Gafter
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Boner
authors.forename: Clara
authors.initials: C
authors.lastname: Wittenberg
authors.forename: David Jonathan
authors.initials: DJ
authors.lastname: van Dijk
mesh_terms: 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
chemical_list: 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