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Abstract: FR-PO150

Uromodulin Deficiency Shapes AKI Severity by Enhanced Oxidative Injury and Stress Response in Proximal Tubules With Early Activation of the Inflammasome

Session Information

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

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • LaFavers, Kaice Arminda, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Micanovic, Radmila, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Sabo, Angela R., Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Khan, Shehnaz, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Winfree, Seth, University of Nebraska System, Lincoln, Nebraska, United States
  • El-Achkar, Tarek M., Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
Background

Uromodulin (Tamm-Horsfall Protein, THP) is uniquely expressed in the kidney and its deficiency aggravates the severity of acute kidney injury (AKI). THP deficiency is a feature of chronic kidney disease (CKD) and is also induced by AKI early after injury. We have shown that loss of THP induces oxidative injury via TRPM2, a redox-regulating cationic channel. Therefore, we propose that THP deficiency observed in CKD and early AKI enhances injury severity by stimulating oxidative stress through TRPM2.

Methods

We used the ischemia reperfusion injury (IRI) model to induce AKI in THP+/+ and THP -/- mice with a 22-minute clamp time and 6 or 24 hour recovery. Single cell RNA sequencing was used to delineate differentially expressed genes and pathways in proximal tubules. Large scale confocal imaging was done on whole kidney sections for spatial analysis. Pharmacological TRPM2 inhibition was achieved using 2-APB. Biochemical assays to measure kidney function, inflammation and gene expression were performed on tissue lysates or serum.

Results

Compared to THP +/+, THP -/- mice had significantly worse kidney injury at 24 hours (serum creatinine) and 6 hours post IRI (increased HAVCR1/KIM1 in S3 proximal tubules). Single cell sequencing of proximal tubules at 6 hours revealed that THP -/- mice had upregulated genes involved in oxidative stress, the integrated stress response (ISR) and regulated cell death pathways. THP -/- mice have increased expression of ATF3, a transcription factor activated by the ISR and IL-1β, a component of the inflammasome/pyroptosis pathway activated by oxidative injury. Inhibition of TRPM2 in THP -/- mice reduced renal oxidative injury 6 hours post IRI.

Conclusion

These results suggest that THP deficiency alters the early course of AKI towards severe injury by increasing the activation of TRPM2, thereby enhancing oxidative injury, stress response and activation of the inflammasome. These findings may have relevance to the increased risk of AKI in states of THP deficiency such as CKD. Increasing THP levels or targeting the pathways induced by its deficiency may have an important impact on improving the course and reducing the severity of AKI.

Funding

  • NIDDK Support