2013 ASCB Annual Meeting, 2013, 02, 85─85

Activating Tranion Factor-3 plays as a novel potent regulator of renal Fibrosis in Streptozotocin-induced diabetic nephropathy model

DaeYeon Lee, GyuHee Kim, Ji Yeon Kim, Keon Jae Park, WonHo Kim

Abstract

Diabetic nephropathy (DN), an end-stage disease of diabetic complication, is characterized by fibrosis of renal glomerulus and tubulointerstitial region. However, the exact molecular mechanisms by which diabetes may initiate or exacerbate chronic kidney disease remain elusive. Here, we investigated whether ATF3 affects diabetic kidney failure and especially, expression of inflammatory factors and macrophage infiltration during the processing of fibrosis. STZ-induced DN rats exhibited renal dysfunction, as evidenced by increased volume of renal glomerulus, thickened basement membrane, and increased mesenterium mass, which are consistent with higher levels of albuminuria, serum creatine, blood glucose, and serum MCP-1 or TNF-α. ATF3 and MCP-1 expression was significantly increased in STZ-treated renal tissue, which is correlated with macrophage infiltration and T-cell activation. As like WT-1, a marker of podocytes, ATF3 was also detected in exosome extraction of urine, correlated with the marked accumulation of ECM molecules. In NRK-52E cells, TNF-α-induced fibrotic gene expression was potentiated by ATF3, which were attenuated by ATF3 siRNA. Also, ATF3 directly activates the tranional activity of MCP-1 promoter by NF-kB-dependent pathway. The macrophage cells cocultured in upper chamber migrated into the TNF-α？treated NRK-52E cells of lower chamber, which were abolished by ATF3 depletion or anti-TNF-α antibody. Here, we know that ATF3 may play as an important regulator of renal fibrosis by enhancing ECM accumulation and macrophage infiltration, and thereby reveals a new aspect of the therapeutic mechanisms involved in DN.

• 본 연구는 질병관리본부 연구개발과제(과제번호 2013-NG64002-00) 연구비를 지원받아 수행되었습니다.
• This research was supported by a fund(code 2013-NG64002-00) by Research of Korea Centers for Disease Control and Prevention.