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Abstract: TH-PO488

Upregulation of miR-382 Contributes to AKI to CKD Transition via the PTEN/AKT Signaling Pathway

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Fang, Yi, Zhongshan Hospital, Fudan University, Shanghai, China, Shanghai, China
  • Wang, Xiaoyan, Zhongshan Hospital, Fudan University, Shanghai, China, Shanghai, China
  • Kuang, Qing, Zhongshan Hospital, Fudan University, Shanghai, China, Shanghai, China
  • Bao, Siyu, Zhongshan Hospital, Fudan University, Shanghai, China, Shanghai, China
  • Xue, Ning, Zhongshan Hospital, Fudan University, Shanghai, China, Shanghai, China
Background

Acute kidney injury (AKI) is recently considered as a critical factor for the development of chronic kidney disease (CKD). But mechanisms driving AKI to CKD transition remain unclear. Previously we have discovered miR-382 as a novel target in TGF-β1-induced epithelial-mesenchymal transition and the development of tubulointerstitial fibrosis after AKI was accompanied with an overwhelmed activation of miR-382.

Methods

In our recent study of aristolochic acid nephropathy (AAN), we exam the effects of genetic absence or pharmacologic inhibition of miR-382 on the expression of NF-κB/PTEN/AKT signaling pathway and renal pathological changes.

Results

Renal fibrosis developed at 14 days after a single dose of aristolochic acid (AA, 10mg/kg,ip) and renal fibrotic lesions getting even more severe at 28 days after AA treatment. Renal abundance of miR-382 was detected increasing until 28 days post AA administration while inhibition of miR-382 partly reversed renal tubulointerstitial fibrosis. The protective effects of anti-miR-382 treatment against fibrosis was also verified in miR-382 KO mice. Protein expression of phosphatase and tensin homolog (PTEN), a target of miR-382, was down-regulated and subsequently its downstream phosphorylated protein kinase B (AKT) signaling pathway was activated during AA induced AKI to CKD transition. Furthermore, we found the up-regulation of miR-382 of renal epithelial cells was in part mediated by activation of NF-kB signaling secondary to AA exposure, with substantial elevation of pro-inflammatory cytokines such as interlukin-1β and tumor necrosis factor-α. In vivo study revealed that either miR-382 knockdown or miR-382 knockout was pivotal for inflammatory suppression. In vitro experiment confirmed that up-regulation of miR-382 in cultured HK-2 cells under AA exposure could be remarkably reversed by NF-kB siRNA.

Conclusion

These data supported a novel mechanism in which AA induced miR-382 up-regulation via NF-kB activation, therefore targeting PTEN/Akt signaling, contributing to the development of renal fibrosis secondary to acute AA related renal toxicity.

Funding

  • Government Support - Non-U.S.