Characterization and Role of SCAI during Renal Fibrosis and Epithelial-to-Mesenchymal Transition

• DOI: 10.1016/j.ajpath.2012.10.009
• Publication Date: 2012-11-22T08:15:19Z
• Authors: Attila Fintha; Ákos Gasparics; Lilla Fang; Zsuzsa Erdei; Péter Hamar; Miklós M. Mózes; Gábor Kökény; László Rosivall; Attila Sebe
• Keywords: 0301 basic medicine; 570; Epithelial-Mesenchymal Transition; Swine; Calcium-Binding Proteins; Microfilament Proteins; Connective Tissue Growth Factor; Down-Regulation; Cadherins; Kidney; Fibrosis; Actins; Rats; 3. Good health; DNA-Binding Proteins; Mice; Protein Transport; 03 medical and health sciences; Animals; Humans; LLC-PK1 Cells; Diabetic Nephropathies; RNA, Messenger; Promoter Regions, Genetic

During progressive tubulointerstitial fibrosis, renal tubular epithelial cells transform into α-smooth muscle actin (SMA)-expressing myofibroblasts via epithelial-to-mesenchymal transition (EMT). SMA expression is regulated by transforming growth factor (TGF)-β1 and cell contact disruption, through signaling events targeting the serum response factor-myocardin-related transcription factor (MRTF) complex. MRTFs are important regulators of fibrosis, tumor cell invasion, and metastasis. Consistent with the role of MRTFs in tumor progression, suppressor of cancer cell invasion (SCAI) was recently identified as a negative regulator of MRTF. Herein, we studied the role of SCAI in a fibrotic EMT model established on LLC-PK1 cells. SCAI overexpression prevented SMA promoter activation induced by TGF-β1. When co-expressed, it inhibited the stimulatory effects of MRTF-A, MRTF-B or the constitutive active forms of RhoA, Rac1, or Cdc42 on the SMA promoter. SCAI interfered with TGF-β1-induced SMA, connective tissue growth factor, and calponin protein expression; it rescued TGF-β1-induced E-cadherin down-regulation. IHC studies on human kidneys showed that SCAI expression is reduced during fibrosis. Kidneys of diabetic rats and mice with unilateral ureteral obstruction depicted significant loss of SCAI expression. In parallel with the decrease of SCAI protein expression, diabetic rat and mouse kidneys with unilateral ureteral obstruction showed SMA expression, as evidenced by using Western blot analysis. Finally, TGF-β1 treatment of LLC-PK1 cells attenuated SCAI protein expression. These data suggest that SCAI is a novel transcriptional cofactor that regulates EMT and renal fibrosis.