ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Please note that you are viewing an archived section from 2021 and some content may be unavailable. To unlock all content for 2021, please visit the archives.

Abstract: FR-OR05

The Long Noncoding RNA GSTM3P1 Is Induced to Exacerbate Ischemic AKI by Antagonizing MicroRNA-668

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Wei, Qingqing, Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Zhou, Jiliang, Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States
Background

Long non-coding RNAs (lncRNAs) are a group of epigenetic regulators that may play important roles in kidney diseases, but the specific LncRNAs involved and the underlying mechanisms are poorly understood. We recently unveiled miR-668 as a potent protective microRNA in ischemic AKI (Wei Q et al. J Clin Invest 128:5448, 2018). By deep sequencing of mir-668-induced silencing complex, we have identified GSTM3P1, a lncRNA, as a potential interactor and regulator of mir-668.

Methods

The expression of GSTM3P1 and its mouse homologue gstm2-ps1 were examined in hypoxia-treated HK2 cells and in mouse kidneys after ischemic AKI. GSTM3P1 was overexpressed in renal cells for functional examination. Proximal tubule-specific gstm2-ps1 knockout mouse model was established to test its role in ischemic AKI in vivo.

Results

GSTM3P1/gstm2-ps1 was markedly induced in the early phase of ischemic AKI models both in vitro and in vivo. In HK2 cells, qPCR indicated a significant increase of GSTM3P1 at 3 hours after 1% O2 treatment. In C57BL/6 mice, gstm2-ps1 was significantly induced in kidneys after 30 minutes of ischemia and 3 hours of reperfusion, which was also accompanied with the suppression of mir-668. In vitro, overexpression of GSTM3P1 led to more renal proximal tubular cell death after ATP depletion. GSTM3P1 overexpression in HEK cells caused significant decrease of the mature form of mir-668. A mir-668 binding site in GSTM3P1 was also confirmed by luciferase assay. We further generated kidney proximal tubule-specific gstm2-ps1 knockout (KO) mouse model. Compared to wild type littermates (WT), the conditional gstm2-ps1 KO mice were significantly protected from renal ischemia-reperfusion injury. Both blood urea nitrogen level [268.18±47.97 mg/dL (WT) vs 174.42±28.65 mg/dL (KO)] and the serum creatinine level [2.45±0.36 mg/dL (WT) vs 1.41±0.27 mg/dL (KO)] were remarkably decreased. Consistently, renal tubular damage and apoptosis were significantly suppressed in KO kidneys. KO kidneys also had lower tubular NGAL.

Conclusion

These results indicate that GSTM3P1/gstm2-ps1 is induced in ischemic AKI, and following induction it mediates tubular cell injury and death by interacting and antagonizing mir-668.

Funding

  • NIDDK Support