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

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

doi:10.3390/ijms22115667

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.

Highlights

Kidney fibrosis is characterized by glomerulosclerosis, vascular sclerosis, and tubulointerstitial fibrosis and is considered the final outcome of chronic kidney disease (CKD) [1,2].As the tubulointerstitial space occupies more than 90% of the kidney, tubulointerstitial fibrosis is an observed pathological process leading to end-stage kidney disease (ESKD) [3]
LJ-4459 to start 1 d prior to ureteral obstruction (UUO) surgery and all mice were euthanized after 7 d of treatment (Figure 1A)
We examined the effect of LJ-4459 on kidney dysfunction and kidney tubular injury in the obstructed kidneys

Summary

Introduction

Kidney fibrosis is characterized by glomerulosclerosis, vascular sclerosis, and tubulointerstitial fibrosis and is considered the final outcome of chronic kidney disease (CKD) [1,2]. As the tubulointerstitial space occupies more than 90% of the kidney, tubulointerstitial fibrosis is an observed pathological process leading to end-stage kidney disease (ESKD) [3]. Tubulointerstitial fibrosis is accompanied by: (i) the infiltration of inflammatory cells, (ii) the activation of fibroblasts, (iii) the accumulation of extracellular matrix (ECM), and (iv) the production of tubular atrophy [4]. Under distress conditions, including ischemia, hypoxia, and inflammation, extracellular ATP levels are increased and rapidly hydrolyzed to adenosine

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