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J. Biol. Chem., Vol. 280, Issue 16, 16354-16359, April 22, 2005

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C/EBP and Its Binding Element Are Required for NFB-induced COX2 Expression Following Hypertonic Stress^*

Jing Chen, Min Zhao, Reena Rao, Hiroyasu Inoue¶, and Chuan-Ming Hao||

From the Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, the ^¶Department of Pharmacology, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan, and the Division of Nephrology, Huashan Hospital, Fudan University, Shanghai 200040, China

NFB plays a critical role mediating COX2 expression in renal medullary interstitial cells (RMICs). The trans-activating ability of NFB can be modified by another nuclear factor C/EBP that can physically bind to NFB and regulate its activity. Because the COX2 promoter also contains a C/EBP site adjacent to the NFB site, the present study examined whether these two transcription factors cooperate to induce COX2 expression following hypertonic stress. Hypertonicity markedly induced COX2 expression in cultured medullary interstitial cells by immunoblot analysis. The tonicity-induced COX2 expression was suppressed by mutant IB (IBm) that blocks NFB activation, demonstrating that tonicity-induced COX2 expression depends on NFB activation. However, mutation of the NFB site in the COX2 promoter failed to abolish tonicity-induced COX2 reporter activity. IB kinase-1 (IKK1) significantly induced COX2-luciferase activity by 2.3-fold (n = 10, p < 0.01); mutation of the NFB site also failed to abolish IKK1-stimulated COX2 reporter activity (86 ± 3.1% of wild type, p > 0.05, n = 4). Interestingly, mutation of the C/EBP site of the COX2 gene significantly reduced both IKK1 and hypertonicity-induced COX2 reporter activity (p < 0.01). To further examine the potential role of C/EBP in tonicity-induced COX2 expression, a dominant negative C/EBP-p20 was transduced into RMICs. C/EBP-p20 markedly suppressed hypertonic (550 mOsm) induction of COX2 (immunoblot) to a similar extent as IBm. No additional suppression was observed when both NFB and C/EBP were simultaneously blocked by IBm and C/EBP-p20. Interestingly, IKK-induced COX2 expression was not only blocked by IBm, but also completely abolished by C/EBP-p20. Further studies demonstrated physical association of C/EBP to NFB p65 by coimmunoprecipitation. Importantly, this interaction between C/EBP and NFB was greatly enhanced following hypertonic stress. These studies indicate C/EBP is required for the transcriptional activation of COX2 by NFB, suggesting a dominant role for the C/EBP pathway in regulating induction of RMIC COX2 by hypertonicity.

Received for publication, September 28, 2004 , and in revised form, February 7, 2005.

^* This work was supported by NIDDK, National Institutes of Health Grant DK065024 (to C.-M. H.) and a Vanderbilt Discovery grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: S3223 MCN, Vanderbilt University Medical Center, Nashville, TN 37232. Tel.: 615-343-9867; Fax: 615-343-4704; E-mail: chuanming.hao{at}vanderbilt.edu.

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