Uremic conditions induce structural weakening of the aorta via MMP-1-mediated degeneration of collagen I

Ansgar Ackerschott (Bonn)1, P. Düsing (Bonn)1, H. Billig (Bonn)1, T. Thiesler (Bonn)2, G. Kristiansen (Bonn)2, S. Zimmer (Bonn)1, F. Jansen (Köln)3, G. Nickenig (Bonn)1, A. Zietzer (Bonn)1

1Universitätsklinikum Bonn Medizinische Klinik und Poliklinik II Bonn, Deutschland; 2Universitätsklinikum Bonn Pathologie Bonn, Deutschland; 3Gemeinschaftspraxis Kardiologie Köln am Neumarkt Köln, Deutschland



Chronic kidney disease (CKD) and aortic aneurysm (AA) share a significant interconnection, impacting each other's progression. CKD not only stands as an independent risk factor for AA development but also notably increases the risk of all-cause mortality post-surgery. Conversely, acute kidney injury subsequent to aortic surgery or intervention serves as a crucial marker, signaling sustained kidney function loss and foretelling future cardiovascular events.

Despite extensive research into the origins of both conditions, the impact of uremic conditions on aortic health remains inadequately understood. Particularly intriguing is the role of uremia in affecting aortic integrity, where matrix metalloproteinases (MMPs) emerge as key players implicated in both renal disease and AA. Our focus is on discerning whether uremic conditions accelerate aneurysmal disease through these molecular mediators.

Methods and results:

Human coronary artery endothelial cells (HCAEC) and human aortic endothelial cells (HAoEC, not shown here) were subjected to simulated conditions of uremia via treatment with 250µM indoxyl sulfate (IS) for 24h. Proteomics analysis revealed significant upregulation of MMP-1 upon uremic injury (A). Increased transcription of MMP-1 as well as inflammatory cytokine IL-1β and cellular adhesion molecules ICAM and VCAM was validated via RTPCR as the expression of MMP-inhibitor TIMP- remained unchanged (B). While ELISA demonstrated elevated release of MMP-1 (C), collagenase assay showed increased degradation of collagen fibers after exposure to IS-treated cells (D). Degradation of collagen matrices by IS-treated cells was attenuated by MMP-inhibitors Doxycyclin and GM6001 (E). Pharmacological antagonism of aryl hydrocarbon receptor 1 with StemRegenin (STR) proved to abrogate MMP-1 activation while improving endothelial migration and proliferation (F). Proteomics analysis and western blot revealed an increase in vesicular MMP-1 after IS treatment (G). Immunofluorescence (IFL)-stainings of the aorta of mice treated with IS exhibited a higher expression level of MMP-1 and increased collagen degradation in the staining against the product Col2 3/4C. Additionally, the circular intima-media area was augmented as a sign of aneurysmal degeneration, whereas monocyte infiltration as quantified by staining against CD 68 remained unchanged (H; DAPI: blue, tissue autofluorescence: green, protein of interest: red). Lastly, IFL-staining of paraffin sections of aortic specimens from patients undergoing replacement surgery for aneurysms of the ascending aorta demonstrated intensified co-localization of MMP-1 to the intimal and adventitial space (I; DAPI: blue, tissue autofluorescence: green, MMP-1: red).


IS triggers an inflammatory response, marked by heightened MMP-1 release facilitated through AHR-1 activation in endothelial cells. This process contributes to the degradation of collagen 1, leading to signs of aneurysmal degeneration of the aorta.

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