Dual Actions of A2A and A3 Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice

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 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.

Metabolomics Provides Insights into Renoprotective Effects of Semaglutide in Obese Mice

“… 29 , 58 It is reported that supplementation of high-fat obesogenic diets with cholic acid or chenodeoxycholic acid inhibits obesity development in mice. 55 Our results confirmed this point exactly.…”

“… 6 , 37 , 54 Alterations in extracellular adenosine signaling can modulate immune responses, inflammatory processes and immunosuppression. 6 , 55 Adenosine activates four specific membrane adenosine receptors, which are named adenosine receptor A1 (A1AR), adenosine receptor A2A (A2AAR), adenosine receptor A2B (A2BAR), and adenosine receptor A3 (A3AR). These ARs belong to the family of G protein-coupled receptors.…”

“…Adenosine analogue has also been reported to improve hyperglycemia status and reduce urinary protein excretion. 6 , 34 , 37 , 54 , 55 However, changes in adenosine levels of obesity-related nephropathy have not been reported. Our results showed that adenosine levels were decreased in obese mice, which were ameliorated after semaglutide administration.…”

The immunomodulatory function of adenosine in sepsis

“…The adenosine antagonist 8-(p-Sulophenyl) theophylline stopped this from happening ( 70 , 91 ). A detailed examination of A3 agonists and antagonists revealed that, although A3 receptors may contribute to the suppression of the oxidative burst, the inhibition is primarily mediated by A2a activation ( 92 , 93 ).…”

Adenosine receptors as emerging therapeutic targets for diabetic kidney disease

“…Since A 3 AR antagonists or A 2A AR agonists protect against DKD, it is reasonable to develop AR modulators with dual action as an A 3 AR antagonist and an A 2A AR agonist in order to have better protective effects against DKD. We showed for the first time that LJ4459, a newly synthesized dual-acting ligand, prevents the progression of tubulointerstitial fibrosis in obstructed kidneys [ 94 ]. It will be interesting to determine whether this dual-acting ligand has better therapeutic efficacy against DKD than an A 3 AR antagonist or an A 2A AR agonist.…”