title: The orphan nuclear receptor SHP attenuates renal fibrosis.
abstract: The accumulation of extracellular matrix proteins is a common feature of fibrotic kidney diseases. Accumulating evidence suggests that TGF-beta 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-beta 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 alpha-smooth muscle actin (alpha-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-beta-stimulated expression of PAI-1, type I collagen, and fibronectin. SHP inhibited TGF-beta- and Smad3-stimulated PAI-1 promoter activities as well as TGF-beta-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 alpha-SMA. In summary, SHP attenuates renal fibrosis in obstructive nephropathy, making its pathway a possible therapeutic target for chronic kidney disease.
authors: Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
authors: Gwon-Soo
authors: GS
authors: Jung
authors: Mi-Kyung
authors: MK
authors: Kim
authors: Mi Sun
authors: MS
authors: Choe
authors: Kyeong-Min
authors: KM
authors: Lee
authors: Hye-Soon
authors: HS
authors: Kim
authors: Young Joo
authors: YJ
authors: Park
authors: Hueng-Sik
authors: HS
authors: Choi
authors: Ki-Up
authors: KU
authors: Lee
authors: Keun-Gyu
authors: KG
authors: Park
authors: In-Kyu
authors: IK
authors: Lee
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D024042:Collagen Type I / Q000235:genetics; D005353:Fibronectins / Q000235:genetics; D005355:Fibrosis; D007668:Kidney / Q000473:pathology*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D000199:Actins; D024042:Collagen Type I; D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D018160:Receptors, Cytoplasmic and Nuclear; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C497787:Smad3 protein, rat; C099713:nuclear receptor subfamily 0, group B, member 2; C498862:Acta2 protein, rat