Smad3-Mediated Upregulation of miR-21 Promotes Renal Fibrosis

• Published in: Journal of the American Society of Nephrology 2011-09, Vol.22 (9), p.1668-1681
• Main Authors: XIANG ZHONG, CHUNG, Arthur C. K, CHEN, Hai-Yong, MENG, Xiao-Ming, LAN, Hui Y
• Format: Article
• Language: English
• Subjects: Animals; Basic Research; Biological and medical sciences; Cell Line; Disease Progression; Gene Knockdown Techniques; Gene Transfer Techniques; Kidneys; Medical sciences; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Nephrology. Urinary tract diseases; Nephrosclerosis - metabolism; Rats; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Transforming Growth Factor beta - metabolism; Up-Regulation; Urinary system involvement in other diseases. Miscellaneous
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2010111168

TGF-β/Smad signaling plays a role in fibrogenesis, but therapies targeting TGF-β are ineffective in treating renal fibrosis. Here, we explored the therapeutic potential of targeting TGF-β-induced microRNA in the progression of renal fibrosis. Microarray analysis and real-time PCR revealed upregulation of miR-21 in tubular epithelial cells (TECs) in response to TGF-β. Lack of Smad3, but not lack of Smad2, prevented cells from upregulating miR-21 in response to TGF-β. In addition, Smad3-deficient mice were protected from upregulation of miR-21 and fibrosis in the unilateral ureteral obstruction model. In contrast, conditional knockout of Smad2 enhanced miR-21 expression and renal fibrosis. Furthermore, ultrasound-microbubble-mediated gene transfer of a miR-21-knockdown plasmid halted the progression of renal fibrosis in established obstructive nephropathy. In conclusion, these data demonstrate that Smad3, but not Smad2, signaling increases expression of miR-21, which promotes renal fibrosis. Inhibition of miR-21 may be a therapeutic approach to suppress renal fibrosis.