title: Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy.
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.
authors: Department of Nephrology, Korea University Ansan Hospital, Ansan, Korea.
authors: Hye Sook
authors: http://orcid.org/0000-0002-9576-6054
authors: HS
authors: Min
authors: Department of Nephrology, Korea University Ansan Hospital, Ansan, Korea.
authors: Jin Joo
authors: http://orcid.org/0000-0001-6779-0113
authors: JJ
authors: Cha
authors: Department of Nephrology, Korea University Ansan Hospital, Ansan, Korea.
authors: Kitae
authors: http://orcid.org/0000-0003-2433-1747
authors: K
authors: Kim
authors: Department of Nephrology, Korea University Ansan Hospital, Ansan, Korea.
authors: Jung Eun
authors: http://orcid.org/0000-0002-5260-7563
authors: JE
authors: Kim
authors: Department of Nephrology, Korea University Ansan Hospital, Ansan, Korea.
authors: Jung Yeon
authors: http://orcid.org/0000-0002-5817-237X
authors: JY
authors: Ghee
authors: Department of Nephrology, Wonkwang University Sanbon Hospital, Gunpo, Korea.
authors: Hyunwook
authors: http://orcid.org/0000-0002-4274-7562
authors: H
authors: Kim
authors: Department of Nephrology, Wonkwang University Sanbon Hospital, Gunpo, Korea.
authors: Ji Eun
authors: http://orcid.org/0000-0002-8299-4816
authors: JE
authors: Lee
authors: Department of Pathology, Inha University Medical College, Incheon, Korea.
authors: Jee Young
authors: http://orcid.org/0000-0003-3224-4029
authors: JY
authors: Han
authors: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
authors: Lak Shin
authors: http://orcid.org/0000-0002-3441-707X
authors: LS
authors: Jeong
authors: Department of Nephrology, Korea University Ansan Hospital, Ansan, Korea.
authors: Dae Ryong
authors: http://orcid.org/0000-0003-0063-2844
authors: DR
authors: Cha
authors: Department of Nephrology, Korea University Ansan Hospital, Ansan, Korea. starch70@korea.ac.kr.
authors: Young Sun
authors: http://orcid.org/0000-0002-4061-386X
authors: YS
authors: Kang
mesh_terms: D000199:Actins / Q000378:metabolism; D000241:Adenosine / Q000494:pharmacology / Q000627:therapeutic use*; D058918:Adenosine A3 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000652:urine; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000517:prevention & control; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: C000588780:2-(2-chloro-6-(3-iodobenzylamino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; D000199:Actins; D058918:Adenosine A3 Receptor Antagonists; D008565:Membrane Proteins; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; C113267:nephrin; C075750:8-epi-prostaglandin F2alpha; D004317:Doxorubicin; D003404:Creatinine; D015237:Dinoprost; D000241:Adenosine
keywords: Adenosine Receptor Antagonist; Adriamycin; Mouse Model; Nephropathy