title: Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy.
abstract: BACKGROUND
  Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs).
  
  
  METHODS
  Experimental diabetes was induced in 6-week-old male Sprague-Dawley (SD) rats by intravenous injection of STZ. Diabetic rats received ramipril (3 mg/kg body weight/day) or vehicle for 32 weeks. AGE-modified rat serum albumin (AGE-RSA) or RSA was intraperitoneally administrated to 6-week-old male SD rats for 16 weeks. RPTCs were stimulated with 100 μg/ml AGE-modified bovine serum albumin (AGE-BSA) or BSA in the presence or absence of 10(-7) M ramiprilat, an inhibitor of angiotensin-converting enzyme or 100 nM BAY11-7082, an IκB-α phosphorylation inhibitor.
  
  
  RESULTS
  AGE and RAGE expression levels and MMP-2 activity in the tubules of diabetic rats was significantly increased in association with increased albuminuria, all of which were blocked by ramipril. AGE infusion induced tubular MMP-2 activation and RAGE gene expression in SD rats. Ramiprilat or BAY11-7082 inhibited the AGE-induced MMP-2 activation or reactive oxygen species generation in RPTCs. Angiotensin II increased MMP-2 gene expression in RPTCs, which was blocked by BAY11-7082.
  
  
  CONCLUSIONS
  Our present study suggests the involvement of AGE-RAGE-induced, RAS-mediated MMP-2 activation in experimental DN. Blockade of AGE-RAGE axis by ramipril may protect against DN partly via suppression of MMP-2.
authors.affiliation: Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011 Japan ; Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Kei
authors.initials: K
authors.lastname: Fukami
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Sho-Ichi
authors.initials: S
authors.lastname: Yamagishi
authors.affiliation: Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia ; Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: Melinda T
authors.initials: MT
authors.lastname: Coughlan
authors.affiliation: Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia ; Department of Glycation and Diabetic Complications, Mater Medical Research Institute, Brisbane, Australia.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Harcourt
authors.affiliation: Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Phillip
authors.initials: P
authors.lastname: Kantharidis
authors.affiliation: Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas-Bonke
authors.affiliation: Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011 Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia ; Department of Glycation and Diabetic Complications, Mater Medical Research Institute, Brisbane, Australia.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
keywords: Advanced glycation end products; Diabetic nephropathy; MMP-2; NF-κB; RAGE; Renin-angiotensin system