Cyclic Nitroxide 4-Methoxy-Tempo May Decrease Serum Amyloid A-Mediated Renal Fibrosis and Reorganise Collagen Networks in Aortic Plaque.

Acute-phase serum amyloid A (SAA) can disrupt vascular homeostasis and is elevated in subjects with diabetes, cardiovascular disease, and rheumatoid arthritis. Cyclic nitroxides (e.g., Tempo) are a class of piperidines that inhibit oxidative stress and inflammation. This study examined whether 4-methoxy-Tempo (4-MetT) inhibits SAA-mediated vascular and renal dysfunction. Acetylcholine-mediated vascular relaxation and aortic guanosine-3',5'-cyclic monophosphate (cGMP) levels both diminished in the presence of SAA. 4-MetT dose-dependently restored vascular function with corresponding increases in cGMP. Next, male ApoE-deficient mice were administered a vehicle (control, 100 µL PBS) or recombinant SAA (100 µL, 120 µg/mL) ± 4-MetT (at 15 mg/kg body weight via i.p. injection) with the nitroxide administered before (prophylaxis) or after (therapeutic) SAA. Kidney and hearts were harvested at 4 or 16 weeks post SAA administration. Renal inflammation increased 4 weeks after SAA treatment, as judged by the upregulation of IFN-γ and concomitant increases in iNOS, p38MAPK, and matrix metalloproteinase (MMP) activities and increased renal fibrosis (Picrosirius red staining) in the same kidneys. Aortic root lesions assessed at 16 weeks revealed that SAA enhanced lesion size (vs. control; p < 0.05), with plaque presenting with a diffuse fibrous cap (compared to the corresponding aortic root from control and 4-MetT groups). The extent of renal dysfunction and aortic lesion size was largely unchanged in 4-MetT-supplemented mice, although renal fibrosis diminished at 16 weeks, and aortic lesions presented with redistributed collagen networks. These outcomes indicate that SAA stimulates renal dysfunction through promoting the IFN-γ-iNOS-p38MAPK axis, manifesting as renal damage and enhanced atherosclerotic lesions, while supplementation with 4-MetT only affected some of these pathological changes.

Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice.

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.