Abstract
Acute serum amyloid A (SAA) is an apolipoprotein that mediates pro-inflammatory and pro-atherogenic pathways. SAA-mediated signalling is diverse and includes canonical and acute immunoregulatory pathways in a range of cell types and organs. This study aimed to further elucidate the roles for SAA in the pathogenesis of vascular and renal dysfunction. Two groups of male ApoE-deficient mice were administered SAA (100 µL, 120 µg/mL) or vehicle control (100 µL PBS) and monitored for 4 or 16 weeks after SAA treatment; tissue was harvested for biochemical and histological analyses at each time point. Under these conditions, SAA administration induced crosstalk between NF-κB and Nrf2 transcriptional factors, leading to downstream induction of pro-inflammatory mediators and antioxidant response elements 4 weeks after SAA administration, respectively. SAA treatment stimulated an upregulation of renal IFN-γ with a concomitant increase in renal levels of p38 MAPK and matrix metalloproteinase (MMP) activities, which is linked to tissue fibrosis. In the kidney of SAA-treated mice, the immunolocalisation of inducible nitric oxide synthase (iNOS) was markedly increased, and this was localised to the parietal epithelial cells lining Bowman’s space within glomeruli, which led to progressive renal fibrosis. Assessment of aortic root lesion at the study endpoint revealed accelerated atherosclerosis formation; animals treated with SAA also showed evidence of a thinned fibrous cap as judged by diffuse collagen staining. Together, this suggests that SAA elicits early renal dysfunction through promoting the IFN-γ-iNOS-p38 MAPK axis that manifests as the fibrosis of renal tissue and enhanced cardiovascular disease.
Highlights
The vascular endothelial monolayer serves as an interface between components of the circulating blood and the tissues in which it supplies; as such, the endothelium plays important roles in normal vascular homeostasis [1]
matrix metalloproteinase (MMP) have been found associated with renal dysfunction by causing renal fibrosis [40]
MMPsense administration to mice 4 weeks after the cessation of serum amyloid A (SAA) treatment showed increased bioluminescent signal intensity in the lower thoracic region and between the hind limbs of the mice (Figure 2A), indicating enhanced MMP activity in response in SAA treatment. This signal was largely absent in control mice MMPsense activation was noted in the tail region for mice administered MMPsense, which is consistent with the recruitment of inflammatory cells that release MMPs at the site of injection injury
Summary
The vascular endothelial monolayer serves as an interface between components of the circulating blood and the tissues in which it supplies; as such, the endothelium plays important roles in normal vascular homeostasis [1]. Endothelial dysfunction represents a systemic pathology linked to cardiovascular and renal diseases [1,3]. Monocyte adherence to the activated endothelium and transmigration into subendothelial spaces lead to the formation of lipidladen foamy macrophages [4], which exacerbate the inflammatory response and promote atheroma formation by recruiting and further stimulating macrophage formation [5]. Endothelial dysfunction, as a result of inappropriate inflammatory activity, negatively impacts the highly vascularised renal system whose functionality is dependent on endothelial integrity [8]. Renal dysfunction is believed to precede various chronic systemic inflammatory diseases such as obesity, metabolic disease, atherosclerosis and cardiovascular disease due to the highly conserved nature of the inflammatory response [9,10,11]
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