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Abstract: SA-PO820

Peroxiredoxin V (PrdxV) Negatively Regulates EGFR/Stat3-Mediated Fibrogenesis via Cys48-Dependent Interaction Between PrdxV and Stat3

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Choi, Hoon In, Chonnam National University Medical School, Gwangju, Korea (the Republic of)
  • Park, Jung Sun, Chonnam National University Medical School, Gwangju, Korea (the Republic of)
  • Kim, Donghyun, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Kim, Injin, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Bae, Eun Hui, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Ma, Seong Kwon, Chonnam National University Medical School, Gwangju, Korea (the Republic of)
  • Kim, Soo Wan, Chonnam National University Medical School, Gwangju, Korea (the Republic of)
Background

Activation of epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 3 (Stat3) signaling pathway has been reported to be associated with renal fibrosis. In addition to the anti-inflammatory effect and the anti-oxidative effect of Peroxiredoxin V (PrdxV), recently it has been shown that PrdxV acts as an anti-fibrotic effector by inhibiting the activity of Stat3 in TGF-β-treated NRK49F cells. However, the relevance and the underlying mechanism of Prdx V to renal pathobiology remains poorly understood.

Methods

To investigate the role of PrdxV in renal fibrosis, we used a transgenic mouse model with PrdxV siRNA expression controlled by U6 promoter (C57BL/6J-Tg(U6-PrdxVsi)1Thlee/Krb; PrdxVsi mice). Both PrdxVwt and PrdxVsi mice were subjected to unilateral ureteral obstruction (UUO) for 7 days (Control vs. UUO group, n = 8 per each group). To understand the molecular mechanism for anti-fibrotic effect of PrdxV, HA-tagged WT PrdxV and C48S PrdxV were transiently transfected into 209/MDCT cells and treated with TGF-β.

Results

We confirmed that the protein level of PrdxV was inversely related to the progression of UUO-induced renal fibrosis. Transgenic PrdxVsi mice exacerbated epithelial-to-mesenchymal transition as well as the increase of oxidative stress by UUO. In the fibrotic kidney of PrdxVsi mouse, knock-down of PrdxV increased Y1068-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 interaction were detected under any conditions.

Conclusion

PrdxV is an anti-fibrotic effector that sustains renal physiology. Direction interaction through Cys48 between PrdxV and Stat3 is a major molecular mechanism.

Funding

  • Government Support - Non-U.S.