Introduction of DNA enzyme for Egr-1 into tubulointerstitial fibroblasts by electroporation reduced interstitial α-smooth muscle actin expression and fibrosis in unilateral ureteral obstruction (UUO) rats

The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-β and Mediates Stimulation of Collagen Gene Expression

“…3 In other studies, a marked increase in lesional fibroblast Egr-1 levels in vivo was found in mice injected with bleomycin. 4 Targeting the Egr-1 gene with specific DNA enzymes in a rat model of ureteral obstruction resulted in down-regulation of myofibroblast marker expression in vivo and reduced fibrosis (63). Furthermore, cardiac hypertrophy and fibrosis induced by isoproterenol infusion were attenuated in Egr-1-null mice compared with littermates (70).…”

“…Elevated Egr-1 expression was detected in synovial fibroblasts in the collagen-rich sub-synovial space in patients with rheumatoid arthritis (61), and in the fibrous caps of atherosclerotic vascular lesions (62). The levels of Egr-1 protein and/or mRNA were elevated in the fibrotic kidneys in rats with ureteral obstruction (63), and in mice with genetic deficiency of type IV collagen, an animal model for Alport syndrome associated with kidney fibrosis (64). The expression of Egr-1 correlated with tissue fibrosis in a model of peritoneal adhesions (65) and in pulmonary artery fibroblasts in hypoxic animals (66).…”

“…In vivo, Egr-1 cDNA delivery in the skin induced localized TGF-␤ production (67). In addition, Egr-1 directly stimulates smooth muscle ␣-actin expression and myofibroblast trans-differentiation (63), as well as transcription of several ECM genes contributing to the development of fibrosis, including, in addition to collagen, fibronectin (52,76), TIMP-1 (77), as well as ICAM-1 and other adhesion molecules (78). In contrast to our present findings, previous studies reported that suppression of collagen synthesis in osteoblast-like cells by FGF2 (79) or by interleukin-1␤ in immortalized chondrocytes was also mediated through Egr-1 (25), suggesting that target gene regulation through Egr-1 was cell type-specific.…”

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

“…8 In connective tissue cells, TGFb1-induced fibrosis in a variety of settings may also be attributed to Egr1. [9][10][11] Thus, TGFb1 appears to be a general effector of Egr1-dependent growth regulation.…”

Exploring RNA interference as a therapeutic strategy for renal disease

“…TGFb1 and GAPDH cDNA were labeled with [a-32 P]dCTP (3000 Ci/mmol; Amersham Biosciences) by the random priming method (Rediprime II, Amersham Biosciences) and hybridization was carried out as described previously. 21 Autoradiographs were obtained and the density of each band was quantified using the laser densitometry (Scanning Imager; Molecular Dynamics, Sunnyvale, CA, USA). These experiments were repeated three times and the density of each band relative to that of GAPDH was calculated.…”