Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy

Diabetology & Metabolic Syndrome

Josephine M Forbes²  Mark E Cooper⁴  Seiya Okuda¹  Vicki Thallas-Bonke⁴  Phillip Kantharidis⁴  Brooke E Harcourt²  Melinda T Coughlan⁵  Sho-ichi Yamagishi³  Kei Fukami⁴ 

[1] Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan;Department of Glycation and Diabetic Complications, Mater Medical Research Institute, Brisbane, Australia;Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan;Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia;Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia

关键词: NF-κB;    RAGE;    MMP-2;    Renin-angiotensin system;    Diabetic nephropathy;    Advanced glycation end products;   

Others  :  1115067
DOI  :  10.1186/1758-5996-6-86

 received in 2014-03-05, accepted in 2014-08-10,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Fukami et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

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