title: Methylglyoxal, a reactive glucose metabolite, increases renin angiotensin aldosterone and blood pressure in male Sprague-Dawley rats.
abstract: BACKGROUND
  The majority of people with diabetes develop hypertension along with increased activity of the renin-angiotensin system. Methylglyoxal, a reactive glucose metabolite, is elevated in diabetic patients. We investigated the effects of methylglyoxal on the renin-angiotensin system and blood pressure.
  
  
  METHODS
  Male Sprague-Dawley rats were treated with a continuous infusion of methylglyoxal with a minipump for 4 weeks. Organs/tissues and cultured vascular smooth muscle cells (VSMCs) were used for molecular studies. High-performance liquid chromatography, Western blotting, and quantitative real-time polymerase chain reaction were used to measure methylglyoxal, proteins, and mRNA, respectively. Small interfering RNA for angiotensinogen and the receptor for advanced glycation endproducts (RAGE) were used to study mechanisms.
  
  
  RESULTS
  Methylglyoxal-treated rats developed a significant increase in blood pressure and plasma levels of aldosterone, renin, angiotensin, and catecholamines. Methylglyoxal level and protein and mRNA for angiotensin, AT1 receptor, adrenergic α1D receptor, and renin were significantly increased in the aorta and/or kidney of methylglyoxal-treated rats, a novel finding. Alagebrium attenuated the above effects of methylgloyxal. Treatment of cultured VSMCs with methylglyoxal or high glucose (25 mM) significantly increased cellular methylglyoxal and protein and mRNA for nuclear factor kappa B (NF-κB), angiotensin, AT1 receptor, and α1D receptor, which were prevented by inhibition of NF-κB, and by alagebrium. Silencing of mRNA for RAGE prevented the increase in NF-kB induced by methylglyoxal. Silencing of mRNA for angiotensinogen prevented the increase in NF-κB, angiotensin, AT1 receptor, and α1D receptor.
  
  
  CONCLUSIONS
  Methylglyoxal activates NF-κB through RAGE and thereby increases renin-angiotensin levels, a novel finding, and a probable mechanism of increase in blood pressure.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Indu
authors.initials: I
authors.lastname: Dhar
authors.forename: Arti
authors.initials: A
authors.lastname: Dhar
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.forename: Kaushik M
authors.initials: KM
authors.lastname: Desai
mesh_terms: D000450:Aldosterone / Q000097:blood*; D000809:Angiotensins / Q000097:blood* / Q000235:genetics; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000097:blood; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006973:Hypertension / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011765:Pyruvaldehyde; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000097:blood* / Q000235:genetics; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000809:Angiotensins; D000959:Antihypertensive Agents; D015415:Biomarkers; D002395:Catecholamines; D016328:NF-kappa B; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013844:Thiazoles; D000450:Aldosterone; D011765:Pyruvaldehyde; C406794:alagebrium; D012083:Renin
keywords: blood pressure; diabetes; hyperglycemia; hypertension; methylglyoxal; receptor for advanced glycation end products; renin-angiotensin-aldosterone system.