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Poly(ADP-Ribose) Polymerase-1 Enhances Transcription of the Profibrotic CCN2 Gene

Hirokazu Okada^*, Tsutomu Inoue^*, Tomohiro Kikuta^*, Nobutaka Kato^*, Yoshihiko Kanno^*, Narumi Hirosawa, Yasushi Sakamoto, Takeshi Sugaya and Hiromichi Suzuki^*

^* Department of Nephrology and Division of Analytical Science, Biomedical Research Center, Saitama Medical University, Saitama; and Research Unit for Organ Regeneration, Riken Kobe Institute, Kobe, Japan

Correspondence: Dr. Hirokazu Okada, Department of Nephrology, Saitama Medical University, 38 Morohongo, Moroyama-machi, Irumagun, Saitama 350-0451, Japan. Phone: 81-49-276-1611; Fax: 81-49-295-7338; E-mail: hirookda{at}saitama-med.ac.jp

Received for publication June 6, 2007. Accepted for publication November 29, 2007.

In the fibrotic kidney, tubular epithelial cells express CCN2, formerly known as connective tissue growth factor. Because little is known about the transcriptional regulation of this profibrotic protein, this study investigated the mechanism underlying epithelial cell–selective upregulation of CCN2 in fibrosis. It was found that a previously unidentified cis-regulatory element located in the promoter of the murine CCN2 gene plays an essential role in basal and TGF-β1–induced gene transcription in tubular epithelial cells; this element acts in conjunction with the Smad-binding element and the basal control element-1. By protein mass fingerprint analysis and de novo sequencing, poly(ADP-ribose) polymerase-1 (PARP-1) was identified as a trans-acting protein factor that binds to this promoter region, which we termed the PARP-1–binding element. In vivo, knockdown of PARP-1 in proximal tubular epithelial cells significantly reduced CCN2 mRNA levels and attenuated interstitial fibrosis in the obstructed kidney. Thus, the PARP-1/PARP-1 binding element complex functions as a nonspecific, fundamental enhancer of both basal and induced CCN2 gene transcription in tubular epithelial cells. This regulatory complex may be a promising target for antifibrotic therapy.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673