Role for cyclic nitroxides in protecting renal function from Serum Amyloid A stimulated renal injury

Abstract

Serum amyloid A (SAA) is an acute-phase apolipoprotein, synthesised in response to pro-inflammatory states and may be a useful biomarker for inflammatory disease within the body. SAA may also contribute to pro-inflammatory signalling, exacerbate pro-atherogenic pathophysiological cascades and induce endothelial dysfunction. Cyclic nitroxides, antioxidants which scavenges free radicals, may mitigate endothelial dysfunction and therefore may provide renoprotective/cardioprotective benefits.

The current study utilises an atherosclerosis-prone murine model (ApoE-/-) and administration of SAA with cyclic nitroxide antioxidant 4-Methoxy-TEMPO co-supplementation. Histological and biochemical studies were conducted to better define the pathophysiological signalling behind SAA-mediated renal injury, pro-atherogenic activity and the effects of cyclic nitroxide antioxidants upon those cascades. Administration of SAA results in renal injury, implicating both inflammatory and immune cascades, notably Nrf2, NF-B, p38 MAPK and IFN-. Upregulation of pro-inflammatory and pro-immune factors were primarily co-localised to the tubular nuclei of the renal nephron with relative sparing of the glomeruli nuclei. Downstream, this led to acutely increased expression of iNOS within the parietal epithelium of the glomeruli and tubular epithelium.

Together, upregulation of the above factors resulted in increased renal fibrosis in the periglomerular and renal interstitium in the long-term. Furthermore, there was an association with increased plaque size and vulnerability with SAA, signifying increased risk of adverse cardiovascular outcomes. Supplementation with 4-Methoxy-TEMPO was unable to dampen SAA signalling nor mitigate SAA-mediated renal injury/dysfunction, however, features of increased plaque stability were observed. Further studies exploring the effects of cyclic nitroxides on plaque stabilisation in models of plaque rupture will be valuable to corroborate the current data.