Abstract
Background
Extracellular cold-inducible RNA-binding protein aggravates acute kidney injury after
renal ischemia/reperfusion. Although extracellular cold-inducible RNA-binding protein
activates triggering receptor expressed on myeloid cells-1, how this receptor and
its antagonism with a novel peptide M3 affects acute kidney injury is poorly understood.
We, therefore, hypothesize that inhibiting the extracellular cold-inducible RNA-binding
protein/triggering receptor expressed on myeloid cells-1 pathway with M3 attenuates
acute kidney injury.
Methods
Wild-type and triggering receptor expressed on myeloid cells-1-/- mice were subjected to bilateral 30-minute renal hilum clamping followed by reperfusion
or sham. After 4 hours, wild-type mice received M3 (10 mg/kg BW) or normal saline
intraperitoneally. After 24 hours, renal tissue and serum were collected for analysis.
Additionally, wild-type mice were subjected to bilateral renal ischemia for 34 minutes
and treated with M3 at 10 mg/kg BW or vehicle at the time of reperfusion. Survival
was monitored for 10 days.
Results
After renal ischemia/reperfusion, triggering receptor expressed on myeloid cells-1
messenger ribonucleic acid expression increased by 9-fold in wild-type mice compared
to sham mice. Wild-type mice also demonstrated significant increases in serum blood
urea nitrogen, creatinine, and interleukin-6 and renal tissue levels of interleukin-6
and neutrophil gelatinase-associated lipocalin after renal ischemia/reperfusion compared
to sham mice. Triggering receptor expressed on myeloid cells-1-/- mice demonstrated significant reductions in serum blood urea nitrogen, creatinine,
and interleukin-6 compared to wild-type mice after renal ischemia/reperfusion. Levels
of renal interleukin-6 and neutrophil gelatinase-associated lipocalin were also significantly
decreased in the kidneys of triggering receptor expressed on myeloid cells-1-/- mice. Furthermore, treatment with M3 in wild-type mice significantly decreased serum
and renal levels of interleukin-6 after renal ischemia/reperfusion. M3 treatment demonstrated
significant reductions in renal messenger ribonucleic acid and protein levels of neutrophil
gelatinase-associated lipocalin, serum blood urea nitrogen and creatinine, and histologic
structural damage as well as apoptosis. Treatment with M3 also increased survival
from 35% to 65% in mice with acute kidney injury.
Conclusion
Triggering receptor expressed on myeloid cells-1 mediates the deleterious effects
of extracellular cold-inducible RNA-binding protein in acute kidney injury after renal
ischemia/reperfusion. The novel extracellular cold-inducible RNA-binding protein/triggering
receptor expressed on myeloid cells-1 pathway antagonist, M3, attenuates acute kidney
injury and has the potential to be developed as a therapeutic agent for acute kidney
injury.
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Article info
Publication history
Published online: March 12, 2022
Accepted:
February 6,
2022
Footnotes
Max Brenner, MD, PhD, and Ping Wang, MD, contributed equally to this work.
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
