Systemic administration of HMG-CoA reductase inhibitor protects the blood-retinal barrier and ameliorates retinal inflammation in type 2 diabetes.
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are frequently used lipid-lowering drugs in type 2 diabetes. Recent emerging evidence suggests that statins protect cardiovascular function via lipid-independent mechanisms. However, the potential role of statins in diabetic retinopathy in type 2 diabetes is largely unclear. In the present study we have investigated the effect of lovastatin on blood-retinal barrier and inflammatory status in the retina of db/db mice and in cultured retinal cells. Male C57BL/KsJ db/db mice were randomly chosen to receive gastric gavage of lovastatin (10mg/kg/day) or vehicle control for 6 weeks. Retinal vascular permeability, the tight junction and inflammation were determined. The results showed that db/db mice at the age of 19 weeks exhibited significantly increased retinal vascular leakage and decreased tight junction protein level in the retina. Moreover, the expression of pro-inflammatory factors, e.g. ICAM-1 and TNF-alpha, was drastically up-regulated in diabetic retina. Lovastatin treatment normalized all of these changes. In cultured bovine retinal capillary endothelial cells (RCECs) and human ARPE-19 cells, lovastatin attenuated the decrease of tight junction protein (occludin) and adherens junction protein (VE-cadherin) expression-induced by TNF-alpha, a major pro-inflammatory cytokine in diabetic retinopathy. Lovastatin also attenuated TNF-alpha expression in RCEC. Towards the mechanism, we showed that lovastatin ameliorated ICAM-1 expression-induced by hypoxia and TNF-alpha in both RCECs and ARPE-19 cells, in part through inhibition of NF-kappaB activation. Taken together, these findings indicate that lovastatin protects blood-retinal barrier in diabetic retinopathy, which is likely via its anti-inflammatory effects.
Li
Jingming
J
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Wang
Joshua J
JJ
Chen
Danyang
D
Mott
Robert
R
Yu
Qiang
Q
Ma
Jian-xing
JX
Zhang
Sarah X
SX
D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008055:Lipids; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D008148:Lovastatin