Intraretinal leakage and oxidation of LDL in diabetic retinopathy.
OBJECTIVE
The pathogenesis of diabetic retinopathy (DR) is not fully understood. Clinical studies suggest that dyslipidemia is associated with the initiation and progression of DR. However, no direct evidence supports this theory.


METHODS
Immunostaining of apolipoprotein B100 (ApoB100, a marker of low-density lipoprotein [LDL]), macrophages, and oxidized LDL was performed in retinal sections from four different groups of subjects: nondiabetic, type 2 diabetic without clinical retinopathy, diabetic with moderate nonproliferative diabetic retinopathy (NPDR), and diabetic with proliferative diabetic retinopathy (PDR). Apoptosis was characterized using the TUNEL assay. In addition, in cell culture studies using in vitro-modified LDL, the induction of apoptosis by heavily oxidized-glycated LDL (HOG-LDL) in human retinal capillary pericytes (HRCPs) was assessed.


RESULTS
Intraretinal immunofluorescence of ApoB100 increased with the severity of DR. Macrophages were prominent only in sections from diabetic patients with PDR. Merged images revealed that ApoB100 partially colocalized with macrophages. Intraretinal oxidized LDL was absent in nondiabetic subjects but present in all three diabetic groups, increasing with the severity of DR. TUNEL-positive cells were present in retinas from diabetic subjects but absent in those from nondiabetic subjects. In cell culture, HOG-LDL induced the activation of caspase, mitochondrial dysfunction, and apoptosis in HRCPs.


CONCLUSIONS
These findings suggest a potentially important role for extravasated, modified LDL in promoting DR by promoting apoptotic pericyte loss.
Wu
Mingyuan
M
Harold Hamm Oklahoma Diabetes Center and the Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Chen
Ying
Y
Wilson
Kenneth
K
Chirindel
Alin
A
Ihnat
Michael A
MA
Yu
Yongxin
Y
Boulton
Michael E
ME
Szweda
Luke I
LI
Ma
Jian-Xing
JX
Lyons
Timothy J
TJ
D000328:Adult; D000368:Aged; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D002199:Capillary Permeability; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D018929:Cell Culture Techniques; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D020287:In Situ Nick-End Labeling; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008875:Middle Aged; D010084:Oxidation-Reduction; D020286:Pericytes / Q000473:pathology; D012160:Retina / Q000378:metabolism*
D053299:Apolipoprotein B-100; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D053148:Caspase 3; D053179:Caspase 7