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

Kei Fukami; Sho-Ichi Yamagishi; Melinda T Coughlan; Brooke E Harcourt; Phillip Kantharidis; Vicki Thallas-Bonke; Seiya Okuda; Mark E Cooper; Josephine M Forbes

doi:10.1186/1758-5996-6-86

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

Diabetol Metab Syndr. 2014 Aug 13;6(1):86. doi: 10.1186/1758-5996-6-86. eCollection 2014.

Authors

Kei Fukami¹, Sho-Ichi Yamagishi², Melinda T Coughlan³, Brooke E Harcourt⁴, Phillip Kantharidis⁵, Vicki Thallas-Bonke⁵, Seiya Okuda⁶, Mark E Cooper⁵, Josephine M Forbes⁴

Affiliations

¹ 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.
² Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
³ Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia ; Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia.
⁴ Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia ; Department of Glycation and Diabetic Complications, Mater Medical Research Institute, Brisbane, Australia.
⁵ Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
⁶ Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011 Japan.

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.

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