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The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis.

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.
AuthorsJiyoun Lee, Inah Hwang, Jung H Lee, Hyuk W Lee, Lak-Shin Jeong, Hunjoo Ha
JournalThe American journal of pathology (Am J Pathol) Vol. 183 Issue 5 Pg. 1488-1497 (Nov 2013) ISSN: 1525-2191 [Electronic] United States
PMID24001475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Chemical References
  • 2-(2-chloro-6-(3-iodobenzylamino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol
  • Adenosine A3 Receptor Antagonists
  • Collagen Type I
  • Fibronectins
  • RNA, Messenger
  • Receptor, Adenosine A3
  • Smad Proteins
  • Thiophenes
  • Transforming Growth Factor beta1
  • Protein-Lysine 6-Oxidase
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Adenosine
Topics
  • Adenosine (pharmacology, therapeutic use)
  • Adenosine A3 Receptor Antagonists (administration & dosage, pharmacology, therapeutic use)
  • Animals
  • Collagen Type I (genetics, metabolism)
  • Epithelial-Mesenchymal Transition (drug effects)
  • Extracellular Matrix (drug effects, metabolism)
  • Extracellular Signal-Regulated MAP Kinases (metabolism)
  • Fibronectins (genetics, metabolism)
  • Fibrosis
  • Gene Expression Regulation (drug effects)
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Kidney Diseases (drug therapy, enzymology, pathology, prevention & control)
  • Kidney Tubules, Proximal (drug effects, enzymology, metabolism, pathology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation (drug effects)
  • Protein-Lysine 6-Oxidase (metabolism)
  • RNA, Messenger (genetics, metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A3 (metabolism)
  • Signal Transduction (drug effects)
  • Smad Proteins (metabolism)
  • Thiophenes (pharmacology, therapeutic use)
  • Transforming Growth Factor beta1 (pharmacology)
  • Ureteral Obstruction (complications, enzymology, pathology)

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