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Downregulation of Smad Transcriptional Corepressors SnoN and Ski in the Fibrotic Kidney: An Amplification Mechanism for TGF-1 Signaling

Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Correspondence to Dr. Youhua Liu, Department of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. Phone: 412-648-8253; Fax: 412-648-1916; E-mail: liuy{at}upmc.edu

ABSTRACT. TGF-1 is a profibrotic cytokine that plays a central role in the onset and progression of chronic renal diseases. The activity of TGF-1 is tightly controlled by multiple mechanisms, in which antagonizing Smad-mediated gene transcription by co-repressors is an important regulatory component. This study examined the expression of Smad transcriptional co-repressors in the fibrotic kidney and investigated their potential functions in controlling TGF-1 response. Western blot analysis demonstrated that the protein levels of Smad transcriptional co-repressors SnoN and Ski were progressively reduced in a time-dependent manner in the fibrotic kidney induced by unilateral ureteral obstruction in mice, whereas renal Smad abundance was relatively unaltered. Consistently, SnoN and Ski staining was diminished in the nuclei of renal tubular epithelium and interstitium after obstructive injury. In vitro, knockdown of SnoN expression by RNA interference in tubular epithelial cells dramatically sensitized their responsiveness to TGF-1 stimulation. Conversely, ectopic expression of exogenous SnoN or Ski after transfection conferred tubular epithelial cell resistance to TGF-1–induced epithelial to myofibroblast transition. Both SnoN and Ski could block Smad-mediated activation of TGF-1–responsive promoter and exhibited additive effect in abrogating the profibrotic actions of TGF-1. These results indicate that as a result of loss of Smad transcriptional co-repressors, the profibrotic TGF-1 signaling in diseased kidney is markedly amplified in a magnitude much greater than previously thought. Therefore, new strategy aimed to increase Smad transcriptional co-repressors expression may be effective in antagonizing TGF-1 signaling and thereby blocking the progression of chronic renal fibrosis.

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