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Kidney Week

Abstract: SA-PO151

Renal IsoLG-Containing Antigen-Presenting Cells Modulate Endothelial Cells of Lymphatic Vessels via ET-3/ERB During Kidney Injury

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Pitzer, Ashley Lauren, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Zhong, Jianyong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Kirabo, Annet, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Kon, Valentina, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Previously, we showed that sodium (Na+) promotes the formation of the lipid oxidation product, isolevuglandins (IsoLGs) in antigen-presenting cells (APCs) which, in turn, have been linked to lymphangiogenesis and systemic hypertension. Lymphangiogenesis accompanies multiple experimental and human kidney diseases. Our recent studies show that albuminuric kidney injury leads to a high Na+ environment within the kidneys and promotes renal accumulation of IsoLGs.

Methods

To induce nephrotoxic injury in mice, we used a sheep anti-glomerular antibody and harvested kidneys 3 weeks later.

Results

We observed a 370% increase in albumin: creatinine ratio, a 30% decrease in GFR, and increased systolic blood pressure (+20.1 mmHg) in nephrotoxin injured vs uninjured controls. Immunostaining of renal F4/80 expression, a macrophage marker, revealed a striking increase in the interstitium of nephrotoxic mice vs controls. Using flow cytometric analysis, nephrotoxin-injured kidneys were found to have elevated IsoLGs in monocytes and dendritic cells when compared to controls. Lymphatic endothelial cells (LECs) co-cultured together with APCs in a high Na+ environment have increased IsoLGs as well as expression of endothelin receptor B (ETB), which are blocked with 2-hydroxybenylamine (2-HOBA) treatment. Additionally, when co-cultured with LECs, dendritic cells have increased IsoLG and expression of vasoactive peptide Endothelin-3 (ET-3) in response to a high Na+ environment. Similarly, these observed increases are blocked with 2-HOBA treatment. Using RNA sequencing data and informatics in LECs co-cultured with APCs, we found high Na+ significantly increased ET-3 in immune cells and ETB receptor in LECs.

Conclusion

These findings were validated using RT-PCR. Taken together, this data suggests LEC uptake of IsoLGs is potentiated by high Na+ environment and interaction with inflammatory immune cells, and IsoLGs may play a role in the ET-3/ETB ligand: receptor intersection and crosstalk with LECs.The work was supported by NIH T32HL144446, 1P01HL116263, K01HL13049, R03HL155041, and R01HL144941.

Funding

  • NIDDK Support