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Abstract: FR-PO961

Arginine Metabolism Regulates the Transcription Factor Nrf2 and Prevents Renal Interstitial Fibrosis Through Tubular Spermidine Production

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Aihara, Seishi, Kyushu University, Fukuoka, Japan
  • Torisu, Kumiko, Kyushu University, Fukuoka, Japan
  • Nakano, Toshiaki, Kyushu University, Fukuoka, Japan
  • Kitazono, Takanari, Kyushu University, Fukuoka, Japan
Background

Our previous research showed that arginase 2 (ARG2) is a mediator of ischemia–reperfusion injury in the kidney through regulation of nitrosative stress. However, the physiologic role of ARG2 or the metabolite polyamines in renal interstitial fibrosis remains poorly understood.

Methods

Metabolic change in kidney fibrosis was examined using unilateral ureteral obstruction (UUO) model mice by mass spectrometry. In human proximal tubule cells (HK-2), changes in expression of ARG2 and its metabolites, polyamines and spermidine (Spd), during oxidative stress were examined. T he effects of Spd on Nrf2 activation and autophagy were investigated. UUO models of wild type and Arg2 knockout (KO) mice were employed and kidney fibrosis was evaluated.

Results

"Arginine and proline metabolism" and "arginine biosynthesis" were most altered in UUO kidney. In HK-2 cells, the expression of ARG2 and polyamines were increased in hydrogen peroxide-treated cells. Furthermore, the polyamines and Spd were decreased in ARG2 knockdown. Spd strongly induced Nrf2, an antioxidant transcription factor, accompanied with induced expression of target genes and also strongly induced autophagic flux. Fibrotic signals such as TGFβ1 and collagen I in renal tubules were suppressed by Spd. The kidney of mice lacking Arg2 showed significantly exacerbated fibrosis and increased expression of collagen I, αSMA and TGFβ compared to the wild type UUO kidney. An activation of Nrf2 and downstream gene expression were suppressed in Arg2 knockout UUO kidneys.

Conclusion

Our data support that arginine metabolism is activated to produce Spd, which activates Nrf2 and autophagy, resulting in a protective effect against kidney fibrosis.