Kidney Week

Abstract: TH-PO0690

Myeloid Cell TRPM2 and Uromodulin (Tamm-Horsfall Protein) Mediate Immune Response and Organ Damage in Sepsis

Session Information

• AKI: Mechanisms - Inflammation and Repair
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Wischmeier, Dillen, Indiana University School of Medicine, Indianapolis, Indiana, United States

Dillen Wischmeier

• Sherman, Emma H., Indiana University School of Medicine, Indianapolis, Indiana, United States

Emma H. Sherman

• Sabo, Angela R., Indiana University School of Medicine, Indianapolis, Indiana, United States

Angela R. Sabo, PhD

• LaFavers, Kaice Arminda, Indiana University School of Medicine, Indianapolis, Indiana, United States

Kaice Arminda LaFavers, PhD

Background

Kidney-derived uromodulin (UMOD) is protective in a mouse model of sepsis, where it promotes proper myeloid cell function in the response to infection. One of the ion channel targets of UMOD inhibition, calcium channel TRPM2, is expressed on myeloid cells and its loss is also protective in a mouse model of sepsis. We therefore hypothesized that the loss of UMOD and/or TRPM2 will disrupt immune cell signaling in sepsis that will reveal important functions for each protein.

Methods

TRPM2 myeloid cell knockout mice ( UMOD ^+/+TRPM2^fl/fl LysM^Cre/+), UMOD knockout mice (UMOD^-/-TRPM2^fl/fl LysM^+/+), TRPM2 myeloid cell/UMOD combined knockout mice (UMOD^-/-TRPM2^fl/fl LysM^Cre/+) and their littermate controls (UMOD^+/+TRPM2^fl/fl LysM^+/+) were used in a cecal slurry model of sepsis. This model causes acute polymicrobial peritonitis that closely resembles what occurs in the clinic, causing hypothermia, hypotension, cytokine release and shock. Animals were euthanized at 10 hours post-injection to collect tissue and serum for imaging and biochemical studies and to assess for signs of illness. Immune cell signaling within the kidney will be analyzed by single-cell RNA-sequencing on the 10X Genomics platform and highly multiplexed imaging of the kidney using Phenocycler technology. Kidney injury will be assessed by measuring serum creatinine and performing histological analysis of the kidney.

Results

The majority of mice were exhibiting minimal early signs of illness at both timepoints, though male TRPM2 myeloid cell/UMOD combined knockout mice (UMOD^-/- TRPM2^fl/fl LysM^Cre/+) were trending toward a higher Murine Modified Sepsis Score at harvest compared to wildtype littermate controls (p = 0.09) . Additional studies to perform scRNA-seq, highly multiplexed imaging, and histological kidney injury analysis from kidney tissue of these mice are ongoing.

Conclusion

Early findings from this study suggest that combined knockout of uromodulin and TRPM2 may be more deleterious in a mouse model of sepsis, though the molecular and cellular mechanisms for this are unclear. Ongoing studies will elucidate the contributions of inflammatory signaling, tissue damage and epithelial-immune cell crosstalk to the observed increase in sepsis severity. Future studies will determine how these changes impact sepsis survival by extending the timeline to later timepoints.

Funding

• NIDDK Support