1. The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis.
- Author
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Lee J, Hwang I, Lee JH, Lee HW, Jeong LS, and Ha H
- 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
- 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., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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