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J. Biol. Chem., Vol. 281, Issue 35, 25344-25355, September 1, 2006

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Heterogeneous Nuclear Ribonucleoprotein K Modulates Angiotensinogen Gene Expression in Kidney Cells^*

Chih-Chang Wei, Shao-Ling Zhang, Yun-Wen Chen, Deng-Fu Guo, Julie R. Ingelfinger, Karol Bomsztyk^¶, and John S. D. Chan¹

From the Centre de Recherche, Centre Hospitalier de l'Université de Montréal-Hôtel-Dieu, Montreal, Quebec H2W 1T8, Canada, the Pediatric Nephrology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114-3117, and the ^¶Department of Medicine, University of Washington, Seattle, Washington 98195

The present studies aimed to identify the 70-kDa nuclear protein that binds to an insulin-responsive element in the rat angiotensinogen gene promoter and to define its action on angiotensinogen gene expression. Nuclear proteins were isolated from rat kidney proximal tubular cells and subjected to two-dimensional electrophoresis. The 70-kDa nuclear protein was detected by Southwestern blotting and subsequently identified by mass spectrometry, which revealed that it was identical to 65-kDa heterogeneous nuclear ribonucleoprotein K (hnRNP K). hnRNP K bound to the insulin-responsive element of the rat angiotensinogen gene was revealed by a gel mobility shift assay and chromatin immunoprecipitation assay. hnRNP K inhibited angiotensinogen mRNA expression and promoter activity. In contrast, hnRNP K down-expression by small interference RNA enhanced angiotensinogen mRNA expression. Moreover, hnRNP K interacted with hnRNP F in pulldown and co-immunoprecipitation assays. Co-transfection of hnRNP K and hnRNP F further suppressed angiotensinogen mRNA expression. Finally, in vitro and in vivo studies demonstrated that high glucose increases and insulin inhibits hnRNP K expression in rat kidney proximal tubular cells. In conclusion, our experiments revealed that hnRNP K is a nuclear protein that binds to the insulin-responsive element of the rat angiotensinogen gene promoter and modulates angiotensinogen gene transcription in the kidney.

Received for publication, March 1, 2006 , and in revised form, July 11, 2006.

^* This work was supported by Canadian Institutes of Health Research Grants MOP-13420 and MOP-62920 (to J. S. D. C.) and MT-14726 (to D.-F. G.), Canadian Diabetes Association Grant 1061, the Kidney Foundation of Canada, and National Institutes of Health Grants HL-48455 (to J. R. I.) DK49578 and GM45134 (to K. B.). 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.

¹ To whom correspondence should be addressed: Centre de Recherche, Centre Hospitalier de l'Université de Montréal-Hôtel-Dieu, Montreal, Quebec H2W 1T8, Canada. Tel.: 514-890-8000 (ext. 15080); Fax: 514-412-7204; E-mail: john.chan{at}umontreal.ca.

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