The orphan nuclear receptor SHP attenuates renal fibrosis.
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.
Jung
Gwon-Soo
GS
Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
Kim
Mi-Kyung
MK
Choe
Mi Sun
MS
Lee
Kyeong-Min
KM
Kim
Hye-Soon
HS
Park
Young Joo
YJ
Choi
Hueng-Sik
HS
Lee
Ki-Up
KU
Park
Keun-Gyu
KG
Lee
In-Kyu
IK
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
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