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...

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Autores principales:	Antony Gao, Sameesh Gupta, Han Shi, Yuyang Liu, Angie L. Schroder, Paul K. Witting, Gulfam Ahmad
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	serum amyloid A atherosclerosis renal dysfunction pro-inflammatory Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/0396dfdfbe164c93bd8812b151f6cc59
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spelling	oai:doaj.org-article:0396dfdfbe164c93bd8812b151f6cc592021-11-25T17:58:03ZPro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice10.3390/ijms2222125821422-00671661-6596https://doaj.org/article/0396dfdfbe164c93bd8812b151f6cc592021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12582https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Acute 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.Antony GaoSameesh GuptaHan ShiYuyang LiuAngie L. SchroderPaul K. WittingGulfam AhmadMDPI AGarticleserum amyloid Aatherosclerosisrenaldysfunctionpro-inflammatoryBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12582, p 12582 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	serum amyloid A atherosclerosis renal dysfunction pro-inflammatory Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	serum amyloid A atherosclerosis renal dysfunction pro-inflammatory Biology (General) QH301-705.5 Chemistry QD1-999 Antony Gao Sameesh Gupta Han Shi Yuyang Liu Angie L. Schroder Paul K. Witting Gulfam Ahmad Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice
description	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.
format	article
author	Antony Gao Sameesh Gupta Han Shi Yuyang Liu Angie L. Schroder Paul K. Witting Gulfam Ahmad
author_facet	Antony Gao Sameesh Gupta Han Shi Yuyang Liu Angie L. Schroder Paul K. Witting Gulfam Ahmad
author_sort	Antony Gao
title	Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice
title_short	Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice
title_full	Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice
title_fullStr	Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice
title_full_unstemmed	Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice
title_sort	pro-inflammatory serum amyloid a stimulates renal dysfunction and enhances atherosclerosis in apo e-deficient mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0396dfdfbe164c93bd8812b151f6cc59
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Pro-Inflammatory Serum Amyloid a Stimulates Renal Dysfunction and Enhances Atherosclerosis in Apo E-Deficient Mice

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