Peroxiredoxin V (PrdxV) negatively regulates EGFR/Stat3-mediated fibrogenesis via a Cys48-dependent interaction between PrdxV and Stat3
2019
Activation of the epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 3 (
Stat3) signaling pathway has been reported to be associated with renal fibrosis. We have recently demonstrated that
peroxiredoxinV (PrdxV) acted as an antifibrotic effector by inhibiting the activity of
Stat3in TGF-β-treated NRK49F cells. However, the underlying mechanism of PrdxV remains poorly understood. To investigate molecular mechanism of PrdxV, we used a transgenic mouse model expressing PrdxV siRNA (PrdxVsi mice) and performed unilateral ureteral obstruction (UUO) for 7 days. 209/MDCT cells were transiently transfected with
HA-taggedWT PrdxV and C48S PrdxV. Transgenic PrdxVsi mice displayed an exacerbated epithelial-to-mesenchymal transition (EMT) as well as an increase in oxidative stress induced by UUO. In the UUO kidney of the PrdxVsi mouse, knockdown of PrdxV increased Tyr1068-specific EGFR and
Stat3phosphorylation, whereas overexpression of WT PrdxV in 209/MDCT cells showed the opposite results. Immunoprecipitation revealed the specific interaction between WT PrdxV and
Stat3in the absence or presence of TGF-β stimulation, whereas no PrdxV-EGFR or C48S PrdxV-
Stat3interactions were detected under any conditions. In conclusion, PrdxV is an antifibrotic effector that sustains
renal physiology. Direct interaction between PrdxV and
Stat3through Cys48 is a major molecular mechanism.
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