ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

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

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO0436

Loss of Stimulator of Interferon Genes (STING) Pathway Does Not Protect the Kidney Against Acute Injury or Inflammatory and Fibrotic Pathways Induced by Folic Acid

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Frikke-Schmidt, Henriette, Janssen Research and Development LLC, Spring House, New Jersey, United States
  • Jouihan, Hani, Janssen Research and Development LLC, Spring House, New Jersey, United States
  • Ho, George, Janssen Research and Development LLC, Spring House, New Jersey, United States
  • Pocai, Alessandro, Janssen Research and Development LLC, Spring House, New Jersey, United States
  • Norquay, Lisa, Janssen Research and Development LLC, Spring House, New Jersey, United States
Background

Acute kidney injury (AKI) greatly increases the risk for developing chronic kidney disease (CKD), but it is currently not well understood how this progression from injury to inflammation and fibrosis takes place. Recently it was discovered that with injury, damaged mitochondria in the kidney can leak mitochondrial DNA into the cytosol, where it activates the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway causing inflammation and fibrosis.
To explore the significance of this pathway in the setting of AKI and CKD transition we induced folic acid nephropathy in mice with no detectable STING activity and evaluated them for kidney function and inflammatory/fibrotic gene expression 7 days after administration.

Methods

23-week-old Goldenticket (Gt)mice (no detectable STING protein due to a missense mutation) and age matched wild type (WT) littermate controls were injected with 250 mg/kg of folic acid. Seven days later plasma, urine, and kidneys were collected for analysis of plasma creatinine, blood urea nitrogen (BUN) and urinary albumin creatinine ratio (uACR). 8 mice were used for both WT and Gt vehicle groups and 11 mice were used for WT and Gt groups treated with folic acid.

Results

In WT control mice folic acid treatment significantly elevated plasma creatinine from 0.27±0.06 to 0.62±0.33mg/dl, BUN levels from 25.1±3.1 to 66.8±21.0mg/dl, and uACR more than doubled from 21.5±13.4 to 53.5±64.3ug/mg. This effect was not statistically different from what was observed in Gt mice (plasma creatinine increasing from 0.25±0.04 to 0.53±0.20mg/dl, BUN increasing from 20.9±1.9 to 54.7±21.1mg/dl, and uACR increasing from 15.9±13.8 to 140.2±313.5ug/mg with folic acid, respectively). Kidney gene expression for genes involved in fibrosis (Tgf-β, Col1a1), inflammation (Tnf, Il6, Il1b), and apoptosis (Bax, Trp53) were all elevated with folic acid treatment. Only Il6 which is a direct effector gene of STING, was significantly decreased in the folic acid treated Gt mice as compared to the folic acid treated WT controls.

Conclusion

Ablation of STING did not protect kidney function, nor did it impact fibrotic or inflammatory gene expression. Our data suggest that the cGAS/STING pathway is not involved in the development of AKI and in the transition to CKD in the folic acid nephropathy model.

Funding

  • Commercial Support