title: Losartan ameliorates progression of glomerular structural changes in diabetic KKAy mice.
abstract: Pathological changes in glomerular structure are typically associated with the progression of diabetic nephropathy. The involvement of angiotensin II (AII) in pathogenesis of diabetic nephropathy has been extensively studied and the therapeutic advantages associated with blockade of renin-angiotensin system (RAS), primarily with angiotensin converting enzyme (ACE) inhibitors, has been well-documented. We studied the effect of RAS blockade with an AII receptor antagonist (losartan) vs. an ACE inhibitor (enalapril) on glomerular lesions in KKAy mice, a model of type 2 diabetes mellitus. Losartan was administered at 3 and 10 mg/kg/day and enalapril at 3 mg/kg/day for 14 weeks in the drinking water. The doses of losartan at 10 mg/kg/day was expected to be equivalent to 3 mg/kg/day of enalapril when considering clinical doses for lowering blood pressure. The dose of 3 mg/kg/day of losartan was selected to compare the efficacy at equivalent dose of enalapril. Histologic observation demonstrated suppression of glomerular mesangial expansion and glomerulosclerosis with exudative lesion in the 10 mg/kg/day losartan group when compared to the untreated diabetic controls. A lesser degree of glomerulosclerosis was also observed with losartan and enalapril treatment at 3 mg/kg/day. Ultrastructural examination of renal glomeruli from the high dose losartan group revealed a decreased degree of effacement and/or irregular arrangement of glomerular podocytic foot process. The beneficial effect of RAS inhibition with the AII receptor antagonist losartan on diabetic glomerular lesions was clearly demonstrated in this study. These findings, therefore, provide mechanistic explanation for the clinical utility of losartan for use in the treatment of diabetic nephropathy in man.
authors.affiliation: Safety Assessment, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Sasaki
authors.forename: Sayuri
authors.initials: S
authors.lastname: Uehara
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Taguchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kemi
authors.forename: Masaru
authors.initials: M
authors.lastname: Nishikibe
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Matsumoto
mesh_terms: D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000648:ultrastructure*; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008820:Mice, Obese; D009929:Organ Size / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D014881:Water Supply
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D004656:Enalapril; D019808:Losartan