Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines.

Tumor growth factor-beta1 (TGF-beta1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-beta1-mediated EMT and fibrosis in kidney injury. We examined apoptosis and EMT in TGF-beta1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-beta1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-beta1 signal pathway proteins and EMT markers. We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-beta1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-beta1-mediated apoptosis and also partially inhibited TGF-beta1-mediated EMT. We showed that EPO treatment suppressed TGF-beta1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-beta1-treated cells. EPO inhibited apoptosis and EMT in TGF-beta1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.

Chen CL ，Chou KJ ，Lee PT ，Chen YS ，Chang TY ，Hsu CY ，Huang WC ，Chung HM ，Fang HC ... -  《-》

A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition.

Yang J ，Dai C ，Liu Y 《JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY》

PINCH-1 promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase.

Li Y ，Dai C ，Wu C ，Liu Y ... -  《JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY》

TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation.

Docherty NG ，O'Sullivan OE ，Healy DA ，Murphy M ，O'neill AJ ，Fitzpatrick JM ，Watson RW ... -  《-》

Erythropoietin decreases renal fibrosis in mice with ureteral obstruction: role of inhibiting TGF-beta-induced epithelial-to-mesenchymal transition.

Park SH ，Choi MJ ，Song IK ，Choi SY ，Nam JO ，Kim CD ，Lee BH ，Park RW ，Park KM ，Kim YJ ，Kim IS ，Kwon TH ，Kim YL ... -  《JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY》