The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway.

Abstract

The TGF-β/Smad3 pathway plays a major role in tissue fibrosis, but the precise mechanisms are not fully understood. Here we identified microRNA miR-433 as an important component of TGF-β/Smad3-driven renal fibrosis. The miR-433 was upregulated following unilateral ureteral obstruction, a model of aggressive renal fibrosis. In vitro, overexpression of miR-433 enhanced TGF-β1-induced fibrosis, whereas knockdown of miR-433 suppressed this response. Furthermore, Smad3, but not Smad2, bound to the miR-433 promoter to induce its expression. Delivery of an miR-433 knockdown plasmid to the kidney by ultrasound microbubble-mediated gene transfer suppressed the induction and progression of fibrosis in the obstruction model. The antizyme inhibitor Azin1, an important regulator of polyamine synthesis, was identified as a target of miR-433. Overexpression of miR-433 suppressed Azin1 expression, while, in turn, Azin1 overexpression suppressed TGF-β signaling and the fibrotic response. Thus, miR-433 is an important component of TGF-β/Smad3-induced renal fibrosis through the induction of a positive feedback loop to amplify TGF-β/Smad3 signaling, and may be a potential therapeutic target in tissue fibrosis.

• Authors: Rong Li, Arthur C K Chung, Yuan Dong, Weiqin Yang, Xiang Zhong, Hui Y Lan
• Journal: Kidney international (Kidney Int) Vol. 84 Issue 6 Pg. 1129-44 (Dec 2013) ISSN: 1523-1755 [Electronic] United States
• PMID: 23868013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• MicroRNAs
• Mirn433 microRNA, mouse
• Smad2 Protein
• Smad2 protein, mouse
• Smad2 protein, rat
• Smad3 Protein
• Smad3 protein, mouse
• Smad3 protein, rat
• Smad7 Protein
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1
• ornithine decarboxylase antizyme inhibitor
• Doxorubicin

Topics

• Animals
• Anti-Glomerular Basement Membrane Disease (genetics, metabolism, pathology)
• Binding Sites
• Carrier Proteins (genetics, metabolism)
• Cell Line
• Disease Models, Animal
• Doxorubicin
• Fibrosis
• Kidney (metabolism, pathology)
• Kidney Diseases (etiology, genetics, metabolism, pathology, prevention & control)
• Male
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Promoter Regions, Genetic
• RNA Interference
• Rats
• Signal Transduction
• Smad2 Protein (deficiency, genetics, metabolism)
• Smad3 Protein (deficiency, genetics, metabolism)
• Smad7 Protein (genetics, metabolism)
• Time Factors
• Transfection
• Transforming Growth Factor beta1 (genetics, metabolism)
• Up-Regulation
• Ureteral Obstruction (complications)