Peroxiredoxin V (PrdxV) negatively regulates EGFR/Stat3-mediated fibrogenesis via a Cys48-dependent interaction between PrdxV and Stat3.

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 peroxiredoxin V (PrdxV) acted as an antifibrotic effector by inhibiting the activity of Stat3 in 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-tagged WT 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 Stat3 phosphorylation, whereas overexpression of WT PrdxV in 209/MDCT cells showed the opposite results. Immunoprecipitation revealed the specific interaction between WT PrdxV and Stat3 in the absence or presence of TGF-β stimulation, whereas no PrdxV-EGFR or C48S PrdxV-Stat3 interactions were detected under any conditions. In conclusion, PrdxV is an antifibrotic effector that sustains renal physiology. Direct interaction between PrdxV and Stat3 through Cys48 is a major molecular mechanism.

Citation

Hoon-In Choi, Dong-Hyun Kim, Jung Sun Park, In Jin Kim, Chang Seong Kim, Eun Hui Bae, Seong Kwon Ma, Tae-Hoon Lee, Soo Wan Kim. Peroxiredoxin V (PrdxV) negatively regulates EGFR/Stat3-mediated fibrogenesis via a Cys48-dependent interaction between PrdxV and Stat3. Scientific reports. 2019 Jun 19;9(1):8751

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PMID: 31217524

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