1. Dual Actions of A 2A and A 3 Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice.
- Author
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Pak ES, Jeong LS, Hou X, Tripathi SK, Lee J, and Ha H
- Subjects
- Adenosine A3 Receptor Agonists chemical synthesis, Adenosine A3 Receptor Agonists chemistry, Animals, Fibrosis, Kidney Diseases etiology, Kidney Diseases metabolism, Kidney Diseases pathology, Ligands, Male, Mice, Ureteral Obstruction complications, Ureteral Obstruction metabolism, Ureteral Obstruction pathology, Adenosine A3 Receptor Agonists pharmacology, Kidney Diseases drug therapy, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A3 metabolism, Ureteral Obstruction drug therapy
- 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), A
1 AR, A2A AR, A2B AR, and A3 AR. A2A AR agonists protect against inflammation, and A3 AR 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 A2A AR agonist and an A3 AR antagonist, 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.- Published
- 2021
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