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  • Title: The differential regulation of Smad7 in kidney tubule cells by connective tissue growth factor and transforming growth factor-beta1.
    Author: Qi W, Chen X, Twigg S, Zhang Y, Gilbert RE, Kelly DJ, Pollock CA.
    Journal: Nephrology (Carlton); 2007 Jun; 12(3):267-74. PubMed ID: 17498122.
    Abstract:
    AIMS: Smad7 is an inhibitory Smad that regulates transforming growth factor-beta (TGF-beta) signaling. Connective tissue growth factor (CTGF) is recognized as a potent downstream mediator of the fibrogenic effects of TGF-beta1. SMAD binding sites have been identified in both TGF-beta and CTGF promoters. The effect of CTGF on Smad7 expression and its role in the regulation of Smad7 induced by TGF-beta1 in renal tubular cells is unknown. METHODS: Human model of proximal tubular cells (HK-2 cells) was used and confirmed using a diabetic rat model. RT-PCR was performed to measure Smad7, TGF-beta1 and Smad2 and ELISA was performed to measure active TGF-beta1. CTGF or TGF-beta1 was silenced in HK-2 cells using siRNA methodology. RESULTS: TGF-beta1 induced Smad7 in a time-dependent manner, peaking at 30 min (P<0.0005) but sustained up to 24 hrs (p<0.005). Conversely, CTGF reduced Smad7, which was maximal at 24 hrs (p<0.05). This was supported by our in vivo data demonstrating that CTGF protein significantly increased while Smad7 mRNA level was reduced in a diabetic rat model. The basal expression level of Smad7 decreased in TGF-beta1 silenced cells compared to cells transfected with non-specific siRNA (p<0.0005). The basal expression level of Smad7 increased in CTGF silenced cells (p<0.05), which was increased by TGF-beta1 (p<0.005). Both mRNA and protein levels of TGF-beta1 decreased in CTGF silenced cells (p<0.05 and p<0.005 respectively) accompanied by reduction in Smad2 mRNA level in CTGF silenced cells. CONCLUSIONS: Smad7 is induced rapidly by TGF-beta1 limiting the response to TGF-beta1. CTGF likely plays a key role in promoting TGF-beta1 activity by decreasing the availability of Smad7 and increasing Smad2.
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