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1. PLoS One. 2012;7(2):e31631. Epub 2012 Feb 17.

High Glucose Decreases Expression and Activity of p-glycoprotein in Cultured
Human Retinal Pigment Epithelium Possibly through iNOS Induction.

Zhang Y, Li C, Sun X, Kuang X, Ruan X.

Departments of Ophthalmology, and Anesthesiology, First Municipal People's
Hospital of Guangzhou, Affiliated Hospital of Guangzhou Medical College,
Guangzhou, China.

Inhibition of p-glycoprotein under hyperglycemic conditions has been reported in
various barrier tissues including blood-brain barrier, intestine, and kidney, and
has been linked to significant clinical complications. However, whether this is
also true for the outer blood-retinal barrier constituted by retinal pigment
epithelium, or has a role in pathogenesis of diabetic retinopathy is not yet
clear. In this study, using cultured human retinal pigment epithelium cell line
D407, we found that high glucose exposure induced a significant decrease in
p-glycoprotein expression both at mRNA and at protein levels, accompanied by an
attenuated p-glycoprotein activity determined by intracellular rhodamine 123
retention. In marked contrast, the expressions of both mRNA and protein levels of
inducible nitrate oxide synthase (iNOS) increased, and were accompanied by
increased extracellular nitrate/nitrite production by Griess reaction. In
addition, mRNA levels of nuclear receptors revealed a decreased expression of
pregnane X receptor after the exposure of high glucose. However, the subsequent
alterations in production of nitrate/nitrite, functional expression of
p-glycoprotein, and mRNA levels of pregnane X receptor were partially blocked
when pretreated with S,S'-1,3-phenylene-bis(1,2-ethanediyl)-bis-isothiourea•2HBr
(PBITU), a selective iNOS inhibitor. Moreover, the effects of PBITU were
antagonized with the addition of L-arginine, a substrate for NO synthesis. Our in
vitro results suggest for the first time that iNOS induction plays a novel role
in decreased p-glycoprotein expression and transport function at the human outer
blood-retinal barrier under hyperglycemic conditions and further support the
concept of inhibiting iNOS pathway as a therapeutic strategy for diabetic
retinopathy.

PMCID: PMC3281955
PMID: 22363694 [PubMed - in process]