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The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis.
Am J Pathol. 2013 Nov; 183(5):1488-1497.AJ

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+Show Affiliations

Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.Departments of Pharmaceutical Science and Bioinspired Science, College of Pharmacy, Global Top 5 Program, Ewha Womans University, Seoul, Republic of Korea.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24001475

Citation

Lee, Jiyoun, et al. "The Selective A3AR Antagonist LJ-1888 Ameliorates UUO-induced Tubulointerstitial Fibrosis." The American Journal of Pathology, vol. 183, no. 5, 2013, pp. 1488-1497.
Lee J, Hwang I, Lee JH, et al. The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis. Am J Pathol. 2013;183(5):1488-1497.
Lee, J., Hwang, I., Lee, J. H., Lee, H. W., Jeong, L. S., & Ha, H. (2013). The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis. The American Journal of Pathology, 183(5), 1488-1497. https://doi.org/10.1016/j.ajpath.2013.07.010
Lee J, et al. The Selective A3AR Antagonist LJ-1888 Ameliorates UUO-induced Tubulointerstitial Fibrosis. Am J Pathol. 2013;183(5):1488-1497. PubMed PMID: 24001475.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis. AU - Lee,Jiyoun, AU - Hwang,Inah, AU - Lee,Jung H, AU - Lee,Hyuk W, AU - Jeong,Lak-Shin, AU - Ha,Hunjoo, Y1 - 2013/08/31/ PY - 2012/11/25/received PY - 2013/07/21/revised PY - 2013/07/25/accepted PY - 2013/9/5/entrez PY - 2013/9/5/pubmed PY - 2014/6/11/medline SP - 1488 EP - 1497 JF - The American journal of pathology JO - Am J Pathol VL - 183 IS - 5 N2 - 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. SN - 1525-2191 UR - https://www.unboundmedicine.com/medline/citation/24001475/The_selective_A3AR_antagonist_LJ_1888_ameliorates_UUO_induced_tubulointerstitial_fibrosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9440(13)00531-2 DB - PRIME DP - Unbound Medicine ER -