Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy.
10.3346/jkms.2016.31.9.1403
- Author:
Hye Sook MIN
1
;
Jin Joo CHA
;
Kitae KIM
;
Jung Eun KIM
;
Jung Yeon GHEE
;
Hyunwook KIM
;
Ji Eun LEE
;
Jee Young HAN
;
Lak Shin JEONG
;
Dae Ryong CHA
;
Young Sun KANG
Author Information
1. Department of Nephrology, Korea University Ansan Hospital, Ansan, Korea. starch70@korea.ac.kr
- Publication Type:Original Article
- Keywords:
Adriamycin;
Nephropathy;
Adenosine Receptor Antagonist;
Mouse Model
- MeSH:
Adenosine*;
Albuminuria;
Animals;
Anoxia;
Body Weight;
Collagen Type IV;
Creatinine;
Doxorubicin;
Eating;
Fibrosis;
Inflammation;
Ischemia;
Kidney;
Mice*;
Oxidative Stress;
Plasma;
Plasminogen Activator Inhibitor 1;
Podocytes;
Proteinuria;
Receptors, Purinergic P1*;
Water
- From:Journal of Korean Medical Science
2016;31(9):1403-1412
- CountryRepublic of Korea
- Language:English
-
Abstract:
The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria.
