Back to Search
Start Over
The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis.
- Source :
-
The American journal of pathology [Am J Pathol] 2013 Nov; Vol. 183 (5), pp. 1488-1497. Date of Electronic Publication: 2013 Aug 31. - Publication Year :
- 2013
-
Abstract
- Adenosine in the normal kidney significantly elevates in response to cellular damage. The renal A3 adenosine receptor (A3AR) is up-regulated under stress, but the therapeutic effects of A3AR antagonists on chronic kidney disease are not fully understood. The present study examined the effect of LJ-1888 [(2R,3R,4S)-2-[2-chloro-6-(3-iodobenzylamino)-9H-purine-9-yl]-tetrahydrothiophene-3,4-diol], a newly developed potent, selective, species-independent, and orally active A3AR antagonist, on unilateral ureteral obstruction (UUO)-induced renal fibrosis. Pretreatment with LJ-1888 inhibited UUO-induced fibronectin and collagen I up-regulation in a dose-dependent manner. Masson's trichrome staining confirmed that LJ-1888 treatment effectively reduced UUO-induced interstitial collagen accumulation. Furthermore, delayed administration of LJ-1888 showed an equivalent therapeutic effect on tubulointerstitial fibrosis to that of losartan. Small-interfering A3AR transfection effectively inhibited transforming growth factor-β1 (TGF-β1)-induced fibronectin and collagen I up-regulation in proximal tubular cells similar to LJ-1888, confirming that the renoprotective effect of LJ-1888 resulted from A3AR blockade. UUO- or TGF-β1-induced c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation decreased significantly after LJ-1888 administration. A3AR blockade reduced UUO- or TGF-β1-induced up-regulation of lysyl oxidase, which induces cross-linking of extracellular matrix, suggesting that LJ-1888 may also regulate extracellular matrix accumulation via post-translational regulation. In conclusion, the present data demonstrate that the A3AR antagonist, LJ-1888, blocked the development and attenuated the progression of renal fibrosis, and they suggest that LJ-1888 may become a new therapeutic modality for renal interstitial fibrosis.<br /> (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adenosine pharmacology
Adenosine A3 Receptor Antagonists administration & dosage
Adenosine A3 Receptor Antagonists pharmacology
Animals
Collagen Type I genetics
Collagen Type I metabolism
Epithelial-Mesenchymal Transition drug effects
Extracellular Matrix drug effects
Extracellular Matrix metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
Fibronectins genetics
Fibronectins metabolism
Fibrosis
Gene Expression Regulation drug effects
JNK Mitogen-Activated Protein Kinases metabolism
Kidney Diseases enzymology
Kidney Diseases pathology
Kidney Tubules, Proximal drug effects
Kidney Tubules, Proximal enzymology
Kidney Tubules, Proximal metabolism
Male
Mice
Mice, Inbred C57BL
Phosphorylation drug effects
Protein-Lysine 6-Oxidase metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction drug effects
Smad Proteins metabolism
Thiophenes pharmacology
Transforming Growth Factor beta1 pharmacology
Ureteral Obstruction enzymology
Ureteral Obstruction pathology
Adenosine therapeutic use
Adenosine A3 Receptor Antagonists therapeutic use
Kidney Diseases drug therapy
Kidney Diseases prevention & control
Kidney Tubules, Proximal pathology
Receptor, Adenosine A3 metabolism
Thiophenes therapeutic use
Ureteral Obstruction complications
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 183
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 24001475
- Full Text :
- https://doi.org/10.1016/j.ajpath.2013.07.010