Smad3-Mediated Upregulation of miR-21 Promotes Renal Fibrosis

TGF-beta/Smad signaling plays a role in fibrogenesis, but therapies targeting TGF-beta are ineffective in treating renal fibrosis. Here, we explored the therapeutic potential of targeting TGF-beta-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-beta. Lack of Smad3, but not lack of Smad2, prevented cells from upregulating miR-21 in response to TGF-beta. 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.