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The orphan nuclear receptor SHP attenuates renal fibrosis

Gwon-Soo Jung1, Mi-Kyung Kim, Mi Sun Choe

  • 1Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.

Journal of the American Society of Nephrology : JASN
|August 1, 2009
PubMed

Insights

Small heterodimer partner (SHP) attenuates kidney fibrosis by inhibiting plasminogen activator inhibitor type 1 (PAI-1) and transforming growth factor-beta (TGF-beta) signaling. Loss of SHP accelerates renal fibrosis, suggesting SHP as a therapeutic target for kidney disease.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pathology

Background:

  • Fibrotic kidney diseases are characterized by extracellular matrix protein accumulation.
  • Transforming growth factor-beta (TGF-beta) and plasminogen activator inhibitor type 1 (PAI-1) are implicated in promoting renal fibrosis.
  • Small heterodimer partner (SHP) is known to repress PAI-1 in the liver via TGF-beta signaling inhibition.

Purpose of the Study:

  • To investigate the role of SHP in the development of renal fibrosis.
  • To determine if SHP can inhibit TGF-beta signaling and PAI-1 expression in the kidney.
  • To explore SHP as a potential therapeutic target for obstructive nephropathy and chronic kidney disease.

Main Methods:

  • Unilateral ureteral obstruction (UUO) model in mice to induce renal fibrosis.
  • Analysis of SHP, PAI-1, collagen I, fibronectin, and alpha-SMA expression in wild-type and SHP-/- mice.
  • Adenovirus-mediated overexpression of SHP in cultured renal cells and in vivo to assess its inhibitory effects on fibrotic markers and TGF-beta/Smad3 signaling.

Main Results:

  • UUO increased PAI-1, collagen I, and fibronectin while decreasing SHP expression.
  • SHP deficiency exacerbated renal fibrosis and increased fibrotic marker expression after UUO.
  • SHP overexpression inhibited TGF-beta-stimulated PAI-1, collagen I, and fibronectin expression, and Smad3 binding to the PAI-1 promoter.

Conclusions:

  • SHP plays a protective role against renal fibrosis in obstructive nephropathy.
  • SHP attenuates renal fibrosis by inhibiting TGF-beta signaling and PAI-1 expression.
  • The SHP pathway represents a potential therapeutic target for chronic kidney disease.

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