대한신장학회

논문분류	춘계학술대회 초록집
제목	The comparative effect of LJ-2698, a highly selective adenosine 3 receptor antagonist and angiotensin receptor blockade on diabetic nephropathy in streptozotocin-induced type 1 diabetic mice
저자	Hye Sook Min * 1, Jin Joo Cha, Ji Eun Lee2, Hyun Wook Kim2, Jung Yeon Ghee1, Ji Ae Yoo1, Ki Tae Kim1, Dae-Ha Kim1, Gyu Sik Choi1, Dae Ryong Cha 1, Jee Young Han3, Young Sun Kang 1
출판정보	2016; 2016(1):
키워드	adenosine 3 receptor antagonist , angiotensin II receptor blockade, diabetic nephropathy
초록	Background: Concentration of adenosine in normal kidney increases markedly in response to cellular damage such as hypoxic injury. Extracellular adenosine binds four adenosine receptor (AR) subtypes including A1, A2A, A2B and A3AR. All four ARs has been detected in renal tissues, and A3AR is known to be up-regulated during renal injury. A recent study reported that A3AR antagonist, LJ1888, attenuated the progression of renal fibrosis in UUO model. Therefore, we investigated the comparative effect of a novel A3AR antagonist LJ-2698 and L158809 (ARB) and their combination on diabetic nephropathy in streptozotocin-induced type 1 diabetic mice. Methods: Type 1 diabetes was developed using STZ injection (50mg/kg IP for 5days) in C57BL6 mice. LJ-2698 was administered at a dose of 10mg/kg/day by gavage for 3months. To compare the effects of LJ-2698 with ARB, other group was treated with LC158809 (1.5mg/kg/d) or treated with both LJ-2698 and LC158809 for 12 weeks. To further define the mechanism of LJ-2698, we performed in vitro experiments using podocyte. Results: As expected, STZ mice showed significantly high levels of glucose and HbA1c, and decreased body weight. LJ-2698 and ARB did not induce any significant changes in metabolic parameters such as plasma insulin levels, HOMA-IR, OGTT and ITT. Interestingly, LJ-2698 significantly decreased plasma and urinary oxidative stress markers determined by 8-isoprostane levels, which levels were not decreased with ARB. Urinary albumin excretion showed a significant decrease in both LJ-2698 and ARB group with a similar potency, and there was an additive decrease in combined treatment with LJ-2698 and ARB group. In addition, urinary nephrin excretion was also significantly decreased in both LJ-2698 and ARB group. In cultured podocytes, A3AR expression was significantly upregulated in high glucose (HG), palmitates (PA) and angiotensin-II (Ang-II) treated conditions. Prior treatment with LJ-2698 markedly suppressed HG, PA and Ang-II-induced activation of TGFb1, MCP-1 and type IV collagen synthesis. Conclusion: Our results provide evidence that A3AR antagonist shows similar renoprotective effects with ARB through protection of podocyte injury. These findings suggest that targeting A3AR may have a new promising potential in diabetic nephropathy.
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