Kidney Week

Abstract: TH-PO0110

Myeloid Cell Deletion of the Cationic Channel TRPM2, a Target of Uromodulin Inhibition, Is Protective in Murine Sepsis

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

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

Dillen Wischmeier

• Richman, Hunter A, Washington University in St Louis, St. Louis, Missouri, United States

Hunter A Richman

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

Emma H. Sherman

• Rhodes, George, Indiana University School of Medicine, Indianapolis, Indiana, United States

George Rhodes, MD

• Jones, Meredith L., Indiana University School of Medicine, Indianapolis, Indiana, United States

Meredith L. Jones

• El-Achkar, Tarek M., Indiana University School of Medicine, Indianapolis, Indiana, United States

Tarek M. El-Achkar, MD, FASN

• Yu, Yan, Washington University in St Louis, St. Louis, Missouri, United States

Yan Yu, PhD

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

Kaice Arminda LaFavers, PhD

Background

Kidney-derived uromodulin is protective in a mouse model of sepsis, where it promotes proper myeloid cell function. An ion channel target of uromodulin inhibition, Ca²⁺ channel TRPM2, is expressed on myeloid cells and plays a role in their function. We hypothesized that uromodulin modulates myeloid cell function in sepsis via TRPM2 and its loss on myeloid cells would be protective.

Methods

A myeloid knockout of TRPM2 (TRPM2^fl/fl LysM^Cre/+) and littermate controls (TRPM2^fl/fl LysM^+/+) were subjected to cecal ligation and puncture (CLP). Tissue and serum were collected for imaging and biochemical studies. Immune cell signaling within the kidney was analyzed by single-cell RNA-sequencing (scRNA-seq; analysis with Seurat and CellChat packages) of purified immune cells and multiplexed analysis of cytokines/chemokines. Bone marrow derived macrophages (BMDM) were generated by harvesting bone marrow and treating with M-CSF. Acidification of BMDM phagolysosomes was measured using a pH sensitive dye loaded into a opsonized particle for phagocytosis.

Results

TRPM2^fl/fl LysM^Cre/+ mice have increased survival and decreased severity at 48 hours post-CLP compared to controls, despite similar bacterial burden. Consistent with previous findings that TRPM2 is required for acidification of phagolysosomes, we found that BMDM from knockout mice had decreased acidification rate and increased time to final pH compared to controls. Both groups had similar final pH. In scRNA-seq of immune cells post-sepsis, we found a reduction in transcriptional markers of immune defense in myeloid and lymphoid cells of TRPM2^fl/fl LysM^Cre/+ mice, suggesting loss of TRPM2 on myeloid cell cells is blocking immune crosstalk to promote tolerance. This was supported by decreased cellular communication observed from knockout neutrophils and monocytes. We measured levels of cytokines and chemokines previously implicated in sepsis progression and found that TRPM2 myeloid cell knockout mice fail to upregulate inflammatory cytokines in sepsis.

Conclusion

Myeloid cell knockout of TRPM2 is protective in sepsis, which could be due to an increase in immune tolerance from changes in pro-inflammatory cytokine release. This work supports the development of myeloid cell TRPM2 as a therapeutic target for sepsis.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025z15m7g01