title: Effects of chronic inhibition of ACE and AT1 receptors on glomerular injury in dahl salt-sensitive rats.
abstract: To elucidate the contribution of the renin-angiontensin system (RAS) to glomerular injury in salt-sensitive hypertension, we investigated the chronic effects of the angiotensin I-converting enzyme inhibitor cilazapril and the angiotensin II type 1-receptor antagonist (AT1a) TCV-116 in Dahl-Iwai rats. Dahl salt-sensitive (S) rats receiving 8% salt diet for 6 wk were simultaneously treated with cilazapril (n = 6), TCV-116 (n = 6), or saline (n = 14). The 8% salt diet markedly increased systolic blood pressure (SBP), urinary protein, and N-acetyl-beta-glucosaminidase (NAG) excretion compared with 0.3% salt-treated S (n = 6) or salt-resistant (n = 6) rats. Although neither cilazapril nor TCV-116 reduced the elevated SBP, TCV-116 significantly lowered urinary protein and NAG excretion. Histologically, 8% salt treatment in S rats induced progressive sclerotic and proliferative glomerular changes, which were ameliorated by both drugs. TCV-116 increased the glomerular diameter. Immunofluorescence demonstrated the increased level of type III collagen in the mesangium of 8% salt-treated S rats, which was completely reversed by TCV-116. Competitive RT-PCR of mRNA extracted from the glomeruli revealed that 8% salt treatment significantly increased the levels of proliferating cell nuclear antigen (PCNA) and platelet-derived growth factor B-chain and that TCV-116 significantly reduced the levels of PCNA and transforming growth factor-beta1 (TGF-beta1). Thus, although the chronic RAS-inhibition in salt-sensitive hypertension exerted a histologically renoprotective effect by both ways without lowering blood pressure, the RAS inhibition due to AT1a had more beneficial advantages of reducing proteinuria and attenuating the levels of glomerular TGF-beta1 and extracellular matrix.
authors.affiliation: Department of Medicine III, Okayama University Medical School, Okayama University, Okayama 700-8558 Japan.
authors.forename: F
authors.initials: F
authors.lastname: Otsuka
authors.forename: T
authors.initials: T
authors.lastname: Yamauchi
authors.forename: H
authors.initials: H
authors.lastname: Kataoka
authors.forename: Y
authors.initials: Y
authors.lastname: Mimura
authors.forename: T
authors.initials: T
authors.lastname: Ogura
authors.forename: H
authors.initials: H
authors.lastname: Makino
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight; D017315:Cilazapril / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011507:Proteinuria; D051381:Rats; D020303:Rats, Inbred Dahl; D012598:Sclerosis; D013777:Tetrazoles; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014556:Urine
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D017315:Cilazapril; D003404:Creatinine; D000118:Acetylglucosaminidase; C077793:candesartan cilexetil