Collagen XVIII/endostatin expression in experimental endotoxemic acute renal failure

Abstract

Acute renal failure (ARF) is a frequent complication of Gram-negative sepsis, with a high risk of mortality. Lipopolysaccharide (LPS)-induced ARF is associated with hemodynamic changes that are strongly influenced by the overproduction of nitric oxide (NO) through the cytokine-mediated up-regulation of inducible NO synthase. LPS-induced reductions in systemic vascular resistance paradoxically culminate in renal vasoconstriction. Collagen XVIII is an important component of the extracellular matrix expressed in basement membranes. Its degradation by matrix metalloproteases, cathepsins and elastases results in the formation of endostatin, claimed to have antiangiogenic activity and to be a prominent vasorelaxing agent. We evaluated the expression of endostatin/collagen XVIII in an endotoxemic ARF model. ARF was induced in C57BL/6 mice by intraperitoneal injection of LPS (10 mg/kg) followed by sacrifice 4 and 12 h later. Kidney tissue was the source of RNA and protein and the subject of histological analysis. As early as 4 h after LPS administration, blood urea, creatinine and NO levels were significantly increased compared to control. Endostatin/collagen XVIII mRNA levels were 0.71 times lower than sham-inoculated mice 4 h after LPS inoculation, returning to normal levels 12 h after LPS inoculation. Immunohistological examination revealed that acute injury caused by LPS leads to an increase of endostatin basement membrane staining in association with the decrease of CD31 endothelial basement membrane staining. These results indicate that in the early phase of endotoxemic ARF the endostatin levels were not regulated by gene expression, but by the metabolism of collagen XVIII

Deletion of myosin light chain kinase in endothelial cells has a minor effect on the lipopolysaccharide‐induced increase in microvascular endothelium permeability in mice

“…3, lower panel). We did not observe kidney tubular dilatation in the mice in response to LPS treatment, in agreement with other studies [30]. Our data suggest that MLCK in ECs does not play an important role in LPS-induced inflammatory injury in lung and kidney tissues in mice.…”

Erythropoietin attenuates LPS-induced microvascular damage in a murine model of septic acute kidney injury

“…These results were also confirmed using an in vivo model of septic acute lung injury [34]. Additionally, the decrease of VEGF/VEGFR-2 expressions post LPS was coincident with the notable reduction of PeCAM-1 expression, which was noticed in peritubular and glomerular endothelium as it has been reported by Cichy et al [35].…”

Role of Serum Levels of Angiogenic Cytokines in Assessment of Angiogenesis after Stem Cell Therapy of Diabetic Patients with Critical Limb Ischemia

“…One of the possible explanations for the increase in endostatin is that it is a compensatory mechanism-an indirect sign of increased vascularization through the pathway of a negative feedback. Endostatin is cleaved from collagen XVIII, a core protein of heparan sulfate proteoglycan in vascular basement membranes, by proteases and metalloproteases such as elastase, matricillin, or cathepsin L that are produced by endothelial cells as a reaction to induced angiogenesis (3,8). Endostatin inhibits VEGF-induced endothelial progenitor cell (EPC) synthesis but also appears to interfere directly with endothelial nitric oxide synthase (eNOS) and targets upstream of its signaling pathway (23,29).…”