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 2019 and some content may be unavailable. To unlock all content for 2019, please visit the archives.

Abstract: FR-PO115

Integrated Stress Response Mediates Epithelial Transport Dysfunction During Septic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Luo, Jing, Nanjing Medical University, Nanjing, China
  • Yuan, Qi, Nanjing Medical University, Nanjing, China
  • Jiang, Lei, Nanjing Medical University, Nanjing, China
  • Yang, Junwei, Nanjing Medical University, Nanjing, China
Background

Septic acute kidney injury (AKI) is a common cause of in hospital morbidity and mortality. Sepsis induced AKI is known to be associated with significant impairment of urine concentration, which requires establishment and maintenance of epithelial transport. However, the pathogenesis of endotoxemic tubular dysfunction with the failure of epithelial transport is poorly understood. Integrated stress response (ISR) is a common adaptive pathway for restoring cellular homeostasis under stress conditions such as infection and hypoxia. Previous studies have demonstrated that ISR is activated in AKI. Therefore, we investigate that ISR plays key roles in epithelial transport dysfunction during septic AKI.

Methods

Male C57BL/6 mice (6-8 weeks, 20–25g) received a single-dose of LPS (E. coli serotype 0111:B4, Sigma, 5 mg/kg) or sterile saline with tail vein injection and were killed at 1,3,6,12,24 and 48h (n=6 per group). To further explore the relationship between epithelial transport and ISR, C57BL/6 mice were treated with saline or ISRIB (ISR inhibitor , Sigma,4 mg/kg) intraperitoneally 30 min after LPS injection and sampling at 3 and 24h. Kidney injury, inflammation, the expression of epithelial transport and ISR were measured.

Results

LPS-AKI model have demonstrated an inflammatory state with increased levels of IL-1β and TNF-α,and serious kidney injury indicated by BUN, plasma NGAL and KIM-1. At the same time, we determined that activation of the eukaryotic translation initiation factor 2-α kinase 2/eukaryotic translation initiation factor 2α (Eif2ak2/Eif2α) axis, which is the key mediator of ISR. We divided epithelial transport into 5 categories: Na+/K+-ATPase, tubular ion transport (ENaC, NKCC2, ROMK, NCC, CLCK), acid-base transport(NHE), glucose and urea transport(SGLT1,2,GLUT1,2,UTA,UTB) and water transport(AQP). The mRNA and protein levels of those transport proteins were all downregulated following ISR activation. ISRIB was an inhibitor of ISR . We found that ISRIB could ameliorate inflammatory state and restore renal function and the expression of those epithelial transport proteins after LPS injection.

Conclusion

ISR mediates the dysfunction of renal epithelial transport during septic AKI.

Funding

  • Government Support - Non-U.S.