Dual actions of a2a and a3 adenosine receptor ligand prevents obstruction-induced kidney fibrosis in mice

Eun Seon Pak, Lak Shin Jeong, Xiyan Hou, Sushil K. Tripathi, Jiyoun Lee, Hunjoo Ha

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Kidney fibrosis is the final outcome of chronic kidney disease (CKD). Adenosine plays a significant role in protection against cellular damage by activating four subtypes of adenosine receptors (ARs), A1AR, A2AAR, A2BAR, and A3AR. A2AAR agonists protect against inflammation, and A3AR antagonists effectively inhibit the formation of fibrosis. Here, we showed for the first time that LJ-4459, a newly synthesized dual-acting ligand that is an A2AAR agonist and an A3AR antag-onist, prevents the progression of tubulointerstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed on 6-week-old male C57BL/6 mice. LJ-4459 (1 and 10 mg/kg) was orally administered for 7 days, started at 1 day before UUO surgery. Pretreatment with LJ-4459 improved kidney morphology and prevented the progression of tubular injury as shown by decreases in urinary kidney injury molecular-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion. Obstruction-induced tubulointerstitial fibrosis was attenuated by LJ-4459, as shown by a decrease in fibrotic protein expression in the kidney. LJ-4459 also inhibited inflammation and oxidative stress in the obstructed kidney, with reduced macrophage infiltration, reduced levels of pro-inflammatory cytokines, as well as reduced levels of reactive oxygen species (ROS). These data demonstrate that LJ-4459 has potential as a therapeutic agent against the progression of tubulointerstitial fibrosis.

Original languageEnglish
Article number5667
JournalInternational Journal of Molecular Sciences
Volume22
Issue number11
DOIs
StatePublished - 1 Jun 2021

Keywords

  • Adenosine
  • Adenosine receptors
  • Chronic kidney disease
  • Fibrosis
  • Inflammation

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