Hyperglycemia induced down-regulation of renal P-glycoprotein expression
Journal
European Journal of Pharmacology
Journal Volume
690
Journal Issue
1-3
Pages
42-50
Date Issued
2012
Author(s)
Abstract
The purpose of this study is to investigate the regulation of P-glycoprotein expression in the kidney under diabetic condition. Renal P-glycoprotein expression was examined in inbred mice with type 1 or type 2 diabetes by Western blotting. The underlying mechanisms of P-glycoprotein regulation were examined in Madin-Darby canine kidney type II (MDCK-II) cells by Western blotting or qRT-PCR. 3H-digoxin uptake was measured for P-glycoprotein activity in cells under various treatments. The results showed that P-glycoprotein expression was lower in kidneys of diabetic mice than in controls. In MDCK-II cells, treatments with insulin or IL-6 did not cause any change in P-glycoprotein expression, whereas TNF-α tended to increase P-glycoprotein expression at a concentration of 1 ng/ml. On the other hand, P-glycoprotein expression was reduced under high glucose conditions (450 mg/dl), while superoxide production was increased, and the reduction in P-glycoprotein expression was abolished by N-acetylcysteine (an antioxidant) and staurosporine (a nonselective PKC inhibitor). Treatment with oxidizing agents (H 2O2, BSO) or PMA (a PKC activator) reduced P-glycoprotein expression. Antioxidant (N-acetylcysteine or glutathione) co-treatment abolished the H2O2-induced and BSO-induced reduction in P-glycoprotein expression, whereas it did not prevent the effect of PMA. The PMA-induced P-glycoprotein down-regulation was prevented by co-treatment of LY333531 (a PKC-β inhibitor). 3H-digoxin levels were higher in MDCK-II cells with high glucose, PMA or H2O2 treatments. In conclusion, P-glycoprotein expression is lower in kidneys of diabetic mice and in MDCK-II cells under high glucose conditions. Hyperglycemia induced reactive oxygen species and activated PKC in MDCK-II cells, leading to the decrease in P-glycoprotein expression. ? 2012 Elsevier B.V.
Subjects
Diabetes; Kidney; P-glycoprotein; PKC; Reactive oxygen species
SDGs
Other Subjects
acetylcysteine; digoxin; digoxin h 3; glucose; glutathione; glycoprotein P; insulin; interleukin 6; oxidizing agent; reactive oxygen metabolite; ruboxistaurin; staurosporine; superoxide; tumor necrosis factor alpha; unclassified drug; animal cell; animal experiment; article; concentration response; controlled study; down regulation; female; hyperglycemia; insulin dependent diabetes mellitus; kidney cell; male; mouse; non insulin dependent diabetes mellitus; nonhuman; priority journal; protein expression; regulatory mechanism; Animals; Biological Transport; Blood Glucose; Body Weight; Cell Membrane; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Digoxin; Dogs; Down-Regulation; Female; Hyperglycemia; Insulin; Interleukin-6; Kidney; Madin Darby Canine Kidney Cells; Male; Mice; P-Glycoprotein; Protein Kinase C; Reactive Oxygen Species; Tumor Necrosis Factor-alpha
Type
journal article