title: 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.
authors.affiliation: Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Inah
authors.initials: I
authors.lastname: Hwang
authors.affiliation: Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jung H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Hyuk W
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea. Electronic address: lakjeong@snu.ac.kr.
authors.forename: Lak-Shin
authors.initials: LS
authors.lastname: Jeong
authors.affiliation: Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea. Electronic address: hha@ewha.ac.kr.
authors.forename: Hunjoo
authors.initials: H
authors.lastname: Ha
mesh_terms: D000241:Adenosine / Q000494:pharmacology / Q000627:therapeutic use*; D058918:Adenosine A3 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000150:complications* / Q000201:enzymology / Q000473:pathology
chemical_list: C000588780:2-(2-chloro-6-(3-iodobenzylamino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; D058918:Adenosine A3 Receptor Antagonists; D024042:Collagen Type I; D005353:Fibronectins; D012333:RNA, Messenger; D043684:Receptor, Adenosine A3; D051785:Smad Proteins; D013876:Thiophenes; D053773:Transforming Growth Factor beta1; D008249:Protein-Lysine 6-Oxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000241:Adenosine