Endothelial pentraxin 3 contributes to murine ischemic acute kidney injury.
Toll-like receptor 4 (TLR4), a receptor for damage-associated molecular pattern molecules and also the lipopolysaccharide receptor, is required for early endothelial activation leading to maximal inflammation and injury during murine ischemic acute kidney injury. DNA microarray analysis of ischemic kidneys from TLR4-sufficient and -deficient mice showed that pentraxin 3 (PTX3) was upregulated only on the former while transgenic knockout of PTX3 ameliorated acute kidney injury. PTX3 was expressed predominantly on peritubular endothelia of the outer medulla of the kidney in control mice. Acute kidney injury increased PTX3 protein in the kidney and the plasma where it may be a biomarker of the injury. Stimulation by hydrogen peroxide, or the TLR4 ligands recombinant human high-mobility group protein B1 or lipopolysaccharide, induced PTX3 expression in the Mile Sven 1 endothelial cell line and in primary renal endothelial cells, suggesting that endothelial PTX3 was induced by pathways involving TLR4 and reactive oxygen species. This increase was inhibited by conditional endothelial knockout of myeloid differentiation primary response gene 88, a mediator of a TLR4 intracellular signaling pathway. Compared to wild-type mice, PTX3 knockout mice had decreased endothelial expression of cell adhesion molecules at 4 h of reperfusion, possibly contributing to a decreased early maladaptive inflammation in the kidneys of knockout mice. At 24 h of reperfusion, PTX3 knockout increased expression of endothelial adhesion molecules when regulatory and reparative leukocytes enter the kidney. Thus, endothelial PTX3 plays a pivotal role in the pathogenesis of ischemic acute kidney injury.
Department of Internal Medicine (Nephrology), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8856, USA.
Jianlin
J
Chen
Martin M
MM
Matzuk
Xin J
XJ
Zhou
Christopher Y
CY
Lu
D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D002097:C-Reactive Protein / Q000378:metabolism*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D007511:Ischemia / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000099153:Pentraxins
D002097:C-Reactive Protein; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; D000099153:Pentraxins; C507780:Myd88 protein, mouse; C493487:Tlr4 protein, mouse