Kidney Week

Abstract: SA-PO1047

Extracellular DNA Traps Are Induced by Medullary Range NaCl, but Not Urea, and Protect Against Bacterial Pyelonephritis In Vivo

Session Information

• Pathology and Lab Medicine - II
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

• 1800 Pathology and Lab Medicine

Authors

• Goldspink, Adrian, University and University Clinic Bonn, Bonn, Germany

Adrian Goldspink,

• Schmitz, Jessica, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany

Jessica Schmitz,

• Babyak, Olena, University and University Clinic Bonn, Bonn, Germany

Olena Babyak,

• Breloh, Anne M., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany

Anne M. Breloh,

• Fleig, Susanne V., University and University Clinic Bonn, Bonn, Germany

Susanne V. Fleig,

• Wagenlehner, Florian, University Giessen Clinic for Urology, Giessen, Germany

Florian Wagenlehner,

• Braesen, Jan H., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany

Jan H. Braesen,

• Kurts, Christian, University and University Clinic Bonn, Bonn, Germany

Christian Kurts,

• Von Vietinghoff, Sibylle, University and University Clinic Bonn, Bonn, Germany

Sibylle Von Vietinghoff,

Background

Excessive NaCl and urea concentrations characterize the kidney medulla. Their effects on innate immune cell death, namely extracellular DNA trap (ET) formation were not known. A role for ET in response to renal bacterial infections had not been defined.

Methods

ET generation and myeloid cell death was studied in varying osmolyte concentrations and pharmacologic modulations of different cell death pathways. ET were studied in murine and human pyelonephritis and functions explored by pharmacologic PAD inhibition and modulation of the renal electrolyte gradient.

Results

Medullary-range NaCl, but not urea, dose-, time- and PAD4-dependently induced ET formation even in the absence of other stimuli. Moderately elevated NaCl promoted myeloid cell apoptosis. NaCl induced myeloid cell calcium influx. Modulation of Na-K ATPase and NCX channel were ineffective. Ca²⁺-free media or Ca²⁺-chelation reduced NaCl-induced apoptosis and ET formation. LPS amplified it. ET of granulocytic and monocytic origin were present in human pyelonephritis kidneys, predominantly in the renal medulla. Citrullinated histone levels were systemically elevated in patients suffering from acute pyelonephritis. PAD4 inhibition prevented renal ET formation and promoted pyelonephritis in mice. Depletion of the renal NaCl gradient by loop diuretic therapy diminished renal medullary ET formation and increased pyelonephritis severity.

Conclusion

Our data demonstrate that renal medullary range NaCl concentrations are novel inducers of programmed myeloid cell death, namely ET formation. PAD4-dependent extracellular DNA traps promote antibacterial host response in the kidney.

Funding

• Government Support – Non-U.S.