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논문분류	춘계학술대회 초록집
제목	ATF3 Plays as a Potent Activator of Macrophage Infiltration and Renal Fibrosis in Streptozotocine-induced Diabetic Rats
저자	Gyu Hee Kim, Won-Ho Kim
출판정보	2013; 2013(1):
키워드	당뇨병신증질환, ATF3, MCP-1/Diabetic nephrophaty, ATF3, MCP-1
초록	Renal tubulointerstitial fibrosis is considered as the final outcome of progressive chronic kidney diseases and is closely associated with peritubular inflammation; however, the exact molecular mechanisms involved in peritubular inflammation- mediated renal fibrosis are still not elusive. We assessed here the role of ATF3 on streptozotocine-induced diabetic kidney failure and especially, signaling of inflammatory factors and macrophage infiltration during the processing of fibrosis. STZ-injected rats exhibited renal dysfunction, as evidenced by increased volume of renal glomerulus, thickened basement membrane, and increased mesenterium mass. ATF3 and MCP-1 expression was correlatively increased in kidney tissue of STZ-injected rats, which is associated with the activation of macrophage infiltration and ECM accumulation. In NRK-52E cells, TNF-α-induced fibrotic gene expression was potentiated by ATF3, which were attenuated by ATF3 siRNA. Also, ATF3 determined TNF-α-induced activation of NF-κB, which subsequently led to increase the expression of several inflammation-related proteins, such as MCP-1, ICAM-1, VCAM-1. The critical roles of ATF3 on the regulation of NF-κB-dependent MCP-1 expression were confirmed by performing luciferase assay using wild-type or mutated MCP-1 promoter constructs. TNF-α-induced transcriptional activation of MCP-1 and their potentiation by ATF3 were detected only in the cells transfected with pMCP-1-514 (enh), which contains two copy of NF-kB binding sites, but not in pMCP-1-514(enh)mutA or pMCP-1-514(enh)mutB-transfected cells. The macrophage cells cocultured in upper chamber were 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.
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