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The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis

Gwon-Soo Jung^*, Mi-Kyung Kim^*, Mi Sun Choe, Kyeong-Min Lee, Hye-Soon Kim^*, Young Joo Park, Hueng-Sik Choi^||, Ki-Up Lee^¶, Keun-Gyu Park^* and In-Kyu Lee

*Department of Internal Medicine and
Department of Pathology, Keimyung University School of Medicine, Daegu, South Korea;
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea;
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea;
^||Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea; and
^¶Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, South Korea

Correspondence: Dr. Keun-Gyu Park, Department of Internal Medicine, Keimyung University School of Medicine, 194 Dongsan-dong, Jung-gu, Daegu, 700-712, South Korea. Phone: +82-53-250-7892; Fax: +82-53-250-8010; E-mail: kgpark{at}dsmc.or.kr; or Dr. In-Kyu Lee, Department of Internal Medicine, Kyungpook National University School of Medicine, 50 Samduk-2ga, Jung-gu, Daegu, 700-721, South Korea. Phone: +82-53-420-5564; Fax: +82-53-420-2046; E-mail: leei{at}knu.ac.kr

Received for publication December 3, 2008. Accepted for publication May 27, 2009.

The accumulation of extracellular matrix proteins is a common feature of fibrotic kidney diseases. Accumulating evidence suggests that TGF-β and plasminogen activator inhibitor type 1 (PAI-1) promote the development of renal fibrosis by stimulating the generation and inhibiting the removal of matrix proteins. The small heterodimer partner (SHP) represses PAI-1 expression in the liver by inhibiting TGF-β signaling, but whether SHP inhibits renal fibrosis is unknown. Here, unilateral ureteral obstruction (UUO) markedly increased the expression of PAI-1, type I collagen, and fibronectin but decreased SHP gene expression. Moreover, in kidneys of SHP–/– mice, the expression of PAI-1, type I collagen, fibronectin and -smooth muscle actin (-SMA) were higher compared with those in kidneys of wild-type mice. In addition, loss of SHP accelerated renal fibrosis after UUO. Adenovirus-mediated overexpression of SHP in cultured rat mesangial cells and renal tubular epithelial cells inhibited TGF-β-stimulated expression of PAI-1, type I collagen, and fibronectin. SHP inhibited TGF-β- and Smad3-stimulated PAI-1 promoter activities as well as TGF-β-stimulated binding of Smad3 to its consensus response element on the PAI-1 promoter. Similarly, in vivo, adenovirus-mediated overexpression of SHP in the kidney inhibited the expression of UUO-induced PAI-1, type I collagen, fibronectin, and -SMA. In summary, SHP attenuates renal fibrosis in obstructive nephropathy, making its pathway a possible therapeutic target for chronic kidney disease.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673