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Endothelial pentraxin 3 contributes to murine ischemic acute kidney injury.

ABSTRACT: 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.

SUBMITTER: Chen J

PROVIDER: S-EPMC3499641 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Endothelial pentraxin 3 contributes to murine ischemic acute kidney injury.

Chen Jianlin J Matzuk Martin M MM Zhou Xin J XJ Lu Christopher Y CY

Kidney international 20120815 11

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 ...[more]

PMID: 22895517

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Project description:BackgroundRecent researches indicate that the intestinal consequences of renal ischemia reperfusion (IR) would predispose to the translocation of gut-derived endotoxin. Here, we designed experiments to test the hypothesis that the gut-derived endotoxin has a potential role in mediating local inflammatory processes in the acutely injured kidney.MethodsRats were performed sham or renal IR surgery (60?min of bilateral renal ischemia, then 24?h of reperfusion) (n?=?5). The intestinal structural and mucosa permeability were evaluated. Serum endotoxin and bacterial load in liver and mesenteric lymph nodes (MLN) were measured. Separate groups were pretreated with oral norfloxacin 20?mg/kg/day or saline for 4?weeks and divided into sham plus saline, sham plus norfloxacin, renal IR plus saline and renal IR plus norfloxacin group. Serum biochemistry and endotoxin were determined. Kidney pathological changes were scored. Protein or mRNA expression of toll-like receptor 4 (TLR4) and proinflammatory mediators were measured in kidney homogenate.ResultsRenal IR led to marked intestinal integrity disruption and increase in intestinal permeability. These are accompanied by low grade of endotoxemia as well as increased bacterial load in liver and MLN. The group pretreated with norfloxacin showed significant attenuation of the increase in serum urea, ALAT, ASAT and endotoxin. The increased renal protein or mRNA of TLR4 and proinflammatory mediators (IL-6 and MCP-1) in the unpretreated animals was significantly attenuated in the norfloxacin-pretreated animals. However, norfloxacin pretreatment did not produce any protective effects on renal tubular integrity.ConclusionsOur results show for the first time that gut-derived endotoxin, resulting from an increased intestinal permeability after severe renal IR, subsequently amplifies intrarenal inflammatory response by activation renal TLR4 signaling. Our study results do not establish that antibiotic administration was effective in improving the overall renal outcome. However, our findings may be the first step to understanding how to tailor therapies to mitigate intrarenal inflammation in select groups of patients.

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Endothelial pentraxin 3 contributes to murine ischemic acute kidney injury.

Publications

Endothelial pentraxin 3 contributes to murine ischemic acute kidney injury.

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