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

• Published in: Experimental & molecular medicine Vol. 50; no. 4; pp. 1 - 14
• Main Authors: Dorotea, Debra, Cho, Ahreum, Lee, Gayoung, Kwon, Guideock, Lee, Junghwa, Sahu, Pramod K., Jeong, Lak Shin, Cha, Dae Ryong, Ha, Hunjoo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2018; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 14/63; 38/77; 631/443/272; 64/110; 64/60; 692/699/1585/104; 82/1; 82/51; 82/80; Adenosine; Angiotensin; Biomedical and Life Sciences; Biomedicine; Diabetes; Diabetes mellitus; Drug therapy; End-stage renal disease; Fibrosis; Hypertrophy; Kidney diseases; Medical Biochemistry; Mitochondria; Molecular Medicine; Oxidative stress; Renin; Rodents; Stem Cells; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0053-x

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, A 1 AR, A 2a AR, A 2b AR, and A 3 AR, are expressed in the kidney, our previous study has demonstrated that a novel, orally active, species-independent, and selective A 3 AR 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 A 3 AR 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 A 3 AR antagonist, may become a novel therapeutic agent against DKD. Diabetic kidney disease: drug successfully targets key protein A therapeutic treatment targeting a protein involved in the progression of diabetic kidney disease (DKD) shows promise in mouse trials. Between 30 and 40 per cent of diabetic patients suffer from DKD, a common cause to fatal end-stage kidney disease. Protein receptors, commonly expressed on cell surfaces throughout the body, play both positive and negative roles in diseases. The A 3 adenosine receptor (A 3 AR) is highly expressed in diabetic kidney tissue, and is linked to disease progression. Hunjoo Ha at Ewha Womans University in Seoul, Republic of Korea, and co-workers demonstrated the positive effect of a novel drug in targeting A 3 AR in mice with DKD. A 12-week treatment of the drug prevented kidney injury, lowered oxidative stress and inflammation, and improved kidney function. It may prove an invaluable drug, particularly in combination with an existing DKD drug.