Orally active, species-independent novel A3 adenosine receptor antagonist protects against kidney injury in db/db mice

Debra Dorotea, Ahreum Cho, Gayoung Lee, Guideock Kwon, Junghwa Lee, Pramod K. Sahu, Lak Shin Jeong, Dae-Ryong Cha, Hunjoo Ha

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and the current pharmacological treatment for DKD is limited to renin-angiotensin system (RAS) inhibitors. Adenosine is detectable in the kidney and is significantly elevated in response to cellular damage. While all 4 known subtypes of adenosine receptors, namely, A1AR, A2aAR, A2bAR, and A3AR, are expressed in the kidney, our previous study has demonstrated that a novel, orally active, species-independent, and selective A3AR antagonist, LJ-1888, ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis. The present study examined the protective effects of LJ-2698, which has higher affinity and selectivity for A3AR than LJ-1888, on DKD. In experiment I, dose-dependent effects of LJ-2698 were examined by orally administering 1.5, 5, or 10 mg/kg for 12 weeks to 8-week-old db/db mice. In experiment II, the effects of LJ-2698 (10 mg/kg) were compared to those of losartan (1.5 mg/kg), which is a standard treatment for patients with DKD. LJ-2698 effectively prevented kidney injuries such as albuminuria, glomerular hypertrophy, tubular injury, podocyte injury, fibrosis, inflammation, and oxidative stress in diabetic mice as much as losartan. In addition, inhibition of lipid accumulation along with increases in PGC1α, a master regulator of mitochondrial biogenesis, were demonstrated in diabetic mice treated with either LJ-2698 or losartan. These results suggest that LJ-2698, a selective A3AR antagonist, may become a novel therapeutic agent against DKD.

Original languageEnglish
Number of pages1
JournalExperimental & molecular medicine
Volume50
Issue number4
DOIs
Publication statusPublished - 2018 Apr 20

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Adenosine A3 Receptor Antagonists
Diabetic Nephropathies
Losartan
Kidney
Wounds and Injuries
Fibrosis
Ureteral Obstruction
Podocytes
Purinergic P1 Receptors
Albuminuria
Organelle Biogenesis
Renin-Angiotensin System
Oxidative stress
Adenosine
Hypertrophy
Angiotensins
Chronic Kidney Failure
Renin
Oxidative Stress
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Orally active, species-independent novel A3 adenosine receptor antagonist protects against kidney injury in db/db mice. / Dorotea, Debra; Cho, Ahreum; Lee, Gayoung; Kwon, Guideock; Lee, Junghwa; Sahu, Pramod K.; Jeong, Lak Shin; Cha, Dae-Ryong; Ha, Hunjoo.

In: Experimental & molecular medicine, Vol. 50, No. 4, 20.04.2018.

Research output: Contribution to journalArticle

Dorotea, Debra ; Cho, Ahreum ; Lee, Gayoung ; Kwon, Guideock ; Lee, Junghwa ; Sahu, Pramod K. ; Jeong, Lak Shin ; Cha, Dae-Ryong ; Ha, Hunjoo. / Orally active, species-independent novel A3 adenosine receptor antagonist protects against kidney injury in db/db mice. In: Experimental & molecular medicine. 2018 ; Vol. 50, No. 4.
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