Abstract: TH-PO0113
Pseudogene-Derived lncRNA GSM3P1/gstm2-ps1 Exacerbates Sepsis-Induced AKI via the Inhibition of Their Parent Genes
Session Information
- AKI: Mechanisms - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Huang, Jing, Augusta University Medical College of Georgia, Augusta, Georgia, United States
- Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States
- Wei, Qingqing, Augusta University Medical College of Georgia, Augusta, Georgia, United States
Background
Long non-coding RNAs (lncRNAs) are critical regulators in various forms of kidney injury. We have identified a pro-injurious lncRNA, GSTM3P1 (human ortholog) / gstm2-ps1 (mouse ortholog), that plays a pathogenic role in ischemic acute kidney injury (AKI).
Methods
Our recent study further demonstrated its detrimental function in sepsis-induced AKI in mice challenged with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP), as well as in cultured proximal tubular cells treated with LPS.
Results
Gstm2-ps1 was transiently upregulated at 3-6 hours after LPS or CLP insults in proximal tubular cells both in vitro and in vivo. Overexpression of GSTM3P1/gstm2-ps1 exacerbated LPS-induced tubular cell apoptosis and oxidative stress. Furthermore, proximal tubule-specific gstm2-ps1 knockout mice were significantly protected against LPS-induced AKI, as evidenced by improved renal function with lower blood urea nitrogen (BUN) and serum creatinine levels. These mice also exhibited reduced tubular apoptosis, decreased KIM-1 expression, diminished proximal tubular NGAL levels, and lower reactive oxygen species (ROS) as shown by DCF staining. Similar protective effects were observed in the CLP-induced AKI model. Mechanistically, overexpression of GSTM3P1/gstm2-ps1 markedly suppressed the protein levels of their parent gene GSTM3/gstm2, while only modestly reducing mRNA levels, suggesting translational repression. Restoration of GSTM3/gstm2 expression rescued proximal tubular cells from LPS-induced apoptosis. RNA pull-down analysis revealed that gstm2-ps1 binds to the RNA-binding protein HuR (ELAVL1), a key regulator of mRNA stability and translation. Overexpression of HuR antagonized gstm2-ps1–mediated repression of gstm2.
Conclusion
Taken together, these findings indicate that the induction of GSTM3P1/gstm2-ps1 exacerbates sepsis-induced AKI by competing for HuR binding, thereby suppressing the translation of detoxifying enzyme GSTM3/gstm2, promoting oxidative stress and tubular cell apoptosis.
Funding
- NIDDK Support