Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes.
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 (LXRα/LXRβ), 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 LXRα(-/-), LXRβ(-/-), and LXRα/β(-/-) 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. LXRα(-/-), LXRβ(-/-), and LXRα/β(-/-) 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.
Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA.
Sugata
S
Hazra
Adil
A
Rasheed
Ashay
A
Bhatwadekar
Xiaoxin
X
Wang
Lynn C
LC
Shaw
Monika
M
Patel
Sergio
S
Caballero
Lilia
L
Magomedova
Nathaniel
N
Solis
Yuanqing
Y
Yan
Weidong
W
Wang
Jeffrey S
JS
Thinschmidt
Amrisha
A
Verma
Qiuhong
Q
Li
Moshe
M
Levi
Carolyn L
CL
Cummins
Maria B
MB
Grant
D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors