| First Author | Hazra S | Year | 2012 |
| Journal | Diabetes | Volume | 61 |
| Issue | 12 | Pages | 3270-9 |
| PubMed ID | 22891211 | Mgi Jnum | J:208503 |
| Mgi Id | MGI:5563622 | Doi | 10.2337/db11-1596 |
| Citation | Hazra S, et al. (2012) Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes. Diabetes 61(12):3270-9 |
| abstractText | Endothelial progenitor cells (EPCs), critical for mediating vascular repair, are dysfunctional in a hyperglycemic and/or hypercholesterolemic environment. Their dysfunction contributes to the progression of diabetic macro- and microvascular complications. Activation of "cholesterol-sensing" nuclear receptors, the liver X receptors (LXRalpha/LXRbeta), protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. We hypothesized that LXR activation with a synthetic ligand would correct diabetes-induced EPC dysfunction and improve diabetic retinopathy. Studies were performed in streptozotocin (STZ)-injected DBA/2J mice fed a high-fat Western diet (DBA/STZ/WD) and treated with the LXR agonist GW3965 and in LXRalpha(-/-), LXRbeta(-/-), and LXRalpha/beta(-/-) mice. Retinas were evaluated for number of acellular capillaries and glial fibrillary acidic protein (GFAP) immunoreactivity. Bone marrow EPCs were analyzed for migratory function and gene expression. Compared with vehicle-treated DBA/STZ/WD mice, GW3965 treated mice showed fewer acellular capillaries and reduced GFAP expression. These mice also exhibited enhanced EPC migration and restoration of inflammatory and oxidative stress genes toward nondiabetic levels. LXRalpha(-/-), LXRbeta(-/-), and LXRalpha/beta(-/-) mice developed acellular capillaries and EPC dysfunction similar to the DBA/STZ/WD mice. These studies support a key role for LXR in retinal and bone marrow progenitor dysfunction associated with type 1 diabetes. LXR agonists may represent promising pharmacologic targets for correcting retinopathy and EPC dysfunction. |
