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Modulation of Soluble Receptor for Advanced Glycation End Products by Angiotensin-Converting Enzyme-1 Inhibition in Diabetic Nephropathy

Josephine M. Forbes^*, Suzanne R. Thorpe, Vicki Thallas-Bonke^*, Josefa Pete^*, Merlin C. Thomas^*, Elizabeth R. Deemer, Sahar Bassal, Assam El-Osta, David M. Long^*, Sianna Panagiotopoulos, George Jerums, Tanya M. Osicka and Mark E. Cooper^*

^* Danielle Alberti Memorial Centre for Diabetes Complications, Wynn Domain; and Epigenetics Laboratory, Baker Heart Research Institute, Melbourne, Australia; Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina; and Department of Endocrinology, Austin and Repatriation Medical Centre, Heidelberg, Australia

Address correspondence to: Dr. Josephine Forbes, Danielle Alberti Memorial Centre for Diabetes Complications, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road, Melbourne, Victoria, 8008, Australia. Phone: 61-3-8532-1456; Fax: 61-3-8532-1288; E-mail: josephine.forbes{at}baker.edu.au

Received for publication January 17, 2005. Accepted for publication April 26, 2005.

Recent studies have identified that first-line renoprotective agents that interrupt the renin-angiotensin system not only reduce BP but also can attenuate advanced glycation end product (AGE) accumulation. This study used in vitro, preclinical, and human approaches to explore the potential effects of these agents on the modulation of the receptor for AGE (RAGE). Bovine aortic endothelial cells that were exposed to the angiotensin-converting enzyme inhibitor (ACEi) ramiprilat in the presence of high glucose demonstrated a significant increase in soluble RAGE (sRAGE) secreted into the medium. In streptozotocin-induced diabetic rats, ramipril treatment (ACEi) at 3 mg/L for 24 wk reduced the accumulation of skin collagen-linked carboxymethyllysine and pentosidine, as well as circulating and renal AGE. Renal gene upregulation of total RAGE (all three splice variants) was observed in ACEi-treated animals. There was a specific increase in the gene expression of the splice variant C-truncated RAGE (sRAGE). There were also increases in sRAGE protein identified within renal cells with ACEi treatment, which showed AGE-binding ability. This was associated with decreases in renal full-length RAGE protein from ACEi-treated rats. Decreases in plasma soluble RAGE that were significantly increased by ACEi treatment were also identified in diabetic rats. Similarly, there was a significant increase in plasma sRAGE in patients who had type 1 diabetes and were treated with the ACEi perindopril. Complexes between sRAGE and carboxymethyllysine were identified in human and rodent diabetic plasma. It is postulated that ACE inhibition reduces the accumulation of AGE in diabetes partly by increasing the production and secretion of sRAGE into plasma.

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