Geoffrion, M., Du, X., Irshad, Zehra, Vanderhyden, B. C., Courville, K., Sui, G., D'Agati, V. D., Ott-Braschi, S., Rabbani, Naila, Thornalley, Paul J., Brownlee, M. and Milne, R. W. (2014) Differential effects of glyoxalase 1 overexpression on diabetic atherosclerosis and renal dysfunction in streptozotocin-treated, apolipoprotein E-deficient mice. Physiological Reports, Volume 2 (Number 6). Article number e12043. doi:doi:10.14814/phy2.12043 ISSN 2051-817X.

Preview

PDF WRAP_phy212043.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial. Download (4Mb) | Preview

Request Changes to record.

Abstract

The reactive dicarbonyls, glyoxal and methylglyoxal (MG), increase in diabetes and may participate in the development of diabetic complications. Glyoxal and MG are detoxified by the sequential activities of glyoxalase 1 (GLO1) and glyoxalase 2. To determine the contribution of these dicarbonyls to the etiology of complications, we have genetically manipulated GLO1 levels in apolipoprotein E-null (Apoe−/−) mice. Male Apoe−/− mice, hemizygous for a human GLO1 transgene (GLO1TGApoe−/− mice) or male nontransgenic Apoe−/− litter mates were injected with streptozotocin or vehicle and 6 or 20 weeks later, aortic atherosclerosis was quantified. The GLO1 transgene lessened streptozotocin (STZ)-induced increases in immunoreactive hydroimidazolone (MG-H1). Compared to nondiabetic mice, STZ-treated GLO1TGApoe−/− and Apoe−/− mice had increased serum cholesterol and triglycerides and increased atherosclerosis at both times after diabetes induction. While the increased GLO1 activity in the GLO1TGApoe−/− mice failed to protect against diabetic atherosclerosis, it lessened glomerular mesangial expansion, prevented albuminuria and lowered renal levels of dicarbonyls and protein glycation adducts. Aortic atherosclerosis was also quantified in 22-week-old, male normoglycemic Glo1 knockdown mice on an Apoe−/− background (Glo1KDApoe−/− mice), an age at which Glo1KD mice exhibit albuminuria and renal pathology similar to that of diabetic mice. In spite of ~75% decrease in GLO1 activity and increased aortic MG-H1, the Glo1KDApoe−/− mice did not show increased atherosclerosis compared to age-matched Apoe−/− mice. Thus, manipulation of GLO1 activity does not affect the development of early aortic atherosclerosis in Apoe−/− mice but can dictate the onset of kidney disease independently of blood glucose levels.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RA Public aspects of medicine R Medicine > RC Internal medicine R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Atherosclerosis, Glyoxalase, Enzymes, Kidneys -- Diseases, Diabetes
Journal or Publication Title:	Physiological Reports
Publisher:	Wiley-Blackwell Publishing Ltd.
ISSN:	2051-817X
Official Date:	June 2014
Dates:	Date Event June 2014 Published 11 June 2014 Available 15 May 2014 Accepted 5 February 2014 Submitted
Volume:	Volume 2
Number:	Number 6
Article Number:	Article number e12043
DOI:	doi:10.14814/phy2.12043
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	28 July 2016
Date of first compliant Open Access:	28 July 2016
Funder:	Heart and Stroke Foundation of Ontario, Juvenile Diabetes Research Foundation (U.K.) (JDRF), British Heart Foundation
Grant number:	T6110 (Ontario), 17-2010-519 (JDRF)

Request changes or add full text files to a record

Repository staff actions (login required)

View Item

Downloads