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Tytuł pozycji:

Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood-Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations.

Tytuł:
Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood-Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations.
Autorzy:
Li P; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Yang Y; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Lin Z; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Hong S; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Jiang L; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Zhou H; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Yang L; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Zhu L; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Liu X; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Liu L; Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Źródło:
International journal of molecular sciences [Int J Mol Sci] 2022 Jul 11; Vol. 23 (14). Date of Electronic Publication: 2022 Jul 11.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Original Publication: Basel, Switzerland : MDPI, [2000-
MeSH Terms:
Bile Ducts*/metabolism
Bile Ducts*/surgery
Bilirubin*/metabolism
Blood-Retinal Barrier*/metabolism
Multidrug Resistance-Associated Proteins*/biosynthesis
Multidrug Resistance-Associated Proteins*/genetics
Animals ; Ligation ; Liver/metabolism ; Rats ; p38 Mitogen-Activated Protein Kinases/metabolism
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Grant Information:
82073922 National Natural Science Foundation of China; 81872930 National Natural Science Foundation of China; 82173884 National Natural Science Foundation of China
Contributed Indexing:
Keywords: bile duct ligation; bilirubin; blood–retinal barrier; liver injury; multidrug resistance-associated protein 1; p38 MAPK
Substance Nomenclature:
0 (Multidrug Resistance-Associated Proteins)
EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RFM9X3LJ49 (Bilirubin)
Y49M64GZ4Q (multidrug resistance-associated protein 1)
Entry Date(s):
Date Created: 20220727 Date Completed: 20220728 Latest Revision: 20220802
Update Code:
20240105
PubMed Central ID:
PMC9318728
DOI:
10.3390/ijms23147666
PMID:
35887010
Czasopismo naukowe
Liver injury is often associated with hepatic retinopathy, resulting from accumulation of retinal toxins due to blood-retinal barrier (BRB) dysfunction. Retinal pigment epithelium highly expresses MRP1/Mrp1. We aimed to investigate whether liver injury affects the function and expression of retinal Mrp1 using bile duct ligation (BDL) rats. Retinal distributions of fluorescein and 2,4-dinitrophenyl-S-glutathione were used for assessing Mrp1 function. BDL significantly increased distributions of the two substrates and bilirubin, downregulated Mrp1 protein, and upregulated phosphorylation of p38 and MK2 in the retina. BDL neither affected the retinal distribution of FITC-dextran nor expressions of ZO-1 and claudin-5, demonstrating intact BRB integrity. In ARPE-19 cells, BDL rat serum or bilirubin decreased MRP1 expression and enhanced p38 and MK2 phosphorylation. Both inhibiting and silencing p38 significantly reversed the bilirubin- and anisomycin-induced decreases in MRP1 protein. Apparent permeability coefficients of fluorescein in the A-to-B direction (P app, A-to-B ) across the ARPE-19 monolayer were greater than P app, B-to-A . MK571 or bilirubin significantly decreased P app, A-to-B of fluorescein. Bilirubin treatment significantly downregulated Mrp1 function and expression without affecting integrity of BRB and increased bilirubin levels and phosphorylation of p38 and MK2 in rat retina. In conclusion, BDL downregulates the expression and function of retina Mrp1 by activating the p38 MAPK pathway due to increased bilirubin levels.
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