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Activation of AMP-activated protein kinase prevents lipotoxicity in retinal pericytes.
- Source :
-
Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2011 Jun 01; Vol. 52 (6), pp. 3630-9. Date of Electronic Publication: 2011 Jun 01. - Publication Year :
- 2011
-
Abstract
- Purpose: The recent FIELD study demonstrated that the lipid-lowering agent fenofibrate significantly reduces the development and progression of diabetic retinopathy (DR). These results suggest that lipids may play a causal role in DR. They also suggest that AMP-activated protein kinase (AMPK) activation could account for these findings given that fenofibrate is an AMPK activator. The authors previously demonstrated that free fatty acids, in addition to hyperglycemia, can induce apoptosis in retinal pericytes (PCs), the first cells lost in the diabetic retina. Incubation with the saturated fatty acid palmitate, but not the monounsaturated fatty acid oleate, elicited cytotoxicity in a manner dependent on oxidative stress, NF-κB activation, and ceramide accumulation. In this study, the authors explored whether AMPK can downregulate these pathways and, in doing so, protect PCs from apoptosis.<br />Methods: PCs were incubated with palmitate or oleate to determine whether the factors previously linked to lipotoxicity were uniquely increased by palmitate. The effects of AMPK activation on these parameters and on apoptosis were concurrently examined.<br />Results: Only palmitate increased NF-κB activation, ceramide and diacylglycerol mass, and apoptosis. Activation of AMPK with AICAR or, where used, expression of a constitutively active AMPK prevented all these effects. In contrast, both palmitate and oleate markedly increased oxidative stress, and the activation of AMPK did not prevent this.<br />Conclusions: AMPK activation prevents the metabolic abnormalities and apoptosis specifically caused by palmitate in cultured PCs. Pharmacologic agents that activate AMPK in the diabetic retina may warrant consideration as a therapeutic option to avert PC apoptosis and to maintain microvascular homeostasis.
- Subjects :
- AMP-Activated Protein Kinases genetics
Acetylcarnitine pharmacology
Adenoviridae genetics
Animals
Apoptosis drug effects
Cattle
Cells, Cultured
Cytoprotection
Diglycerides metabolism
Electron Spin Resonance Spectroscopy
Enzyme Activation
Gene Expression Regulation, Enzymologic physiology
In Situ Nick-End Labeling
NF-kappa B metabolism
Oxidative Stress drug effects
Pericytes enzymology
Sphingolipids metabolism
AMP-Activated Protein Kinases metabolism
Oleic Acid toxicity
Palmitates toxicity
Pericytes drug effects
Retinal Vessels cytology
Subjects
Details
- Language :
- English
- ISSN :
- 1552-5783
- Volume :
- 52
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Investigative ophthalmology & visual science
- Publication Type :
- Academic Journal
- Accession number :
- 21345991
- Full Text :
- https://doi.org/10.1167/iovs.10-5784