1. MO550: Vascular Cells Senescence and Modifications in NRF2 Pathway in a Model of URaEMIC Vascular Calcification
- Author
-
Jonas Laget, Sam Hobson, Karen Muyor, Flore Duranton, Irene Cortijo, Piotr Bartochowski, Bernard Jover, Anne Dominique Lajoix, Peter Stenvinkel, Angel Argiles Ciscart, Karolina Kublickiene, and Nathalie Gayrard
- Subjects
Transplantation ,Nephrology - Abstract
BACKGROUND AND AIMS Vascular dysfunction including vascular calcification (VC), is a consequence of ageing and chronic kidney disease (CKD) that increase the risk of cardiovascular events. Accumulation of senescent cells in arteries can lead to structural and functional alterations and contributes to increased arterial stiffness, reduced compliance and impaired contractility. We tested the hypothesis that senescent cells in the arterial wall are involved in the pathophysiology of vascular calcification in a rat model of CKD and VC induced by a high phosphate diet and vitamin D supplementation. METHOD Eight-week-old Sprague–Dawley rats underwent subtotal nephrectomy (SNx, n = 18), or no surgery (Control, n = 6). Eight weeks after, control animals (n = 6) and part of the SNx group (n = 6) were maintained on the standard diet while the remaining rats underwent a 4-week VC-diet, where a standard diet was supplemented with high phosphate and 1-hydroxy-vitamin D at a dose of 0.1 µg/day (SNx 0.1 group, n = 6) or 0.4 µg/day (SNx 0.4 group, n = 6). At the end of the protocol, renal function, blood pressure and VC (von Kossa) were studied. mRNA and protein expressions of cellular senescence markers (p16, p21, yH2AX), antioxidants (NRF2, Nqo-1), VC inducers/inhibitors and osteoblastic transition drivers were assessed by qPCR, immunohistochemistry (IHC), or immunofluorescence (IF). Correlations between mRNA or protein levels and VC were computed for the VC-diets animals (n = 12). RESULTS A decrease in creatinine clearance (P CONCLUSION In our rat model of induced VC associated with CKD, NRF2 and downstream targets expression was increased in thoracic aorta, confirming the link between NRF2 and VC. This might be a response mechanism as observed with other ‘protective’ factors with increased mRNA expression in this model (data not presented here). Furthermore, we observed that cellular senescence was clearly associated with VC. The co-labelling for p16 and yH2AX in some vascular cells in the media layer, exclusively observed in calcified aortas, is another clue that highlights the link between VC and vascular cell senescence.
- Published
- 2022