The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis
AUTOR(ES)
Jung, Gwon-Soo
FONTE
American Society of Nephrology
RESUMO
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 α-smooth muscle actin (α-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 α-SMA. In summary, SHP attenuates renal fibrosis in obstructive nephropathy, making its pathway a possible therapeutic target for chronic kidney disease.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2754099Documentos Relacionados
- A transcriptional inhibitor targeted by the atypical orphan nuclear receptor SHP
- The Orphan Nuclear Receptor SHP Inhibits Hepatocyte Nuclear Factor 4 and Retinoid X Receptor Transactivation: Two Mechanisms for Repression
- Synergistic activation of the human orphan nuclear receptor SHP gene promoter by basic helix–loop–helix protein E2A and orphan nuclear receptor SF-1
- Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP)
- Novel receptor interaction and repression domains in the orphan receptor SHP.
