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Vascular calcification is accelerated by hyponatremia and low osmolality condition via activating Rac1-Akt pathway

ABSTRACT: Hyponatremia, one of the most frequently observed electrolyte disorders in patients with chronic kidney disease (CKD), is associated with increased mortality. Lower sodium concentrations or low osmolar conditions are shown to induce cell damages via apoptosis and oxidative stress, both of accelerate vascular calcification (VC), a critical phenotype of CKD patients. It is unknown whether hyponatremia or low osmolar condition plays roles in the pathogenesis of VC.Human vascular smooth muscle cells (VSMCs) were cultured with calcifying medium, which was supplemented high calcium and phosphate. Concentrations of sodium in the culture media were further modified to determine the impacts of osmotic pressure on VC. Microarray analysis of VSMCs revealed low osmolality activated Rac1-Akt pathway and reduced expression of NCX1, which is calcium-sodium exchanger.Lower osmolality including hyponatremic condition promotes high-phosphate-induced VC through multiple cellular processes including Rac1-Akt pathway activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237847 | GEO | 2023/07/25

REPOSITORIES: GEO

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Project description:Vascular Calcification (VC) is a life threatening cardiovascular complication that accounts for high death rates particularly in association with diabetes, atherosclerosis and Chronic Kidney Disease (CKD. during VC, Vascular Smooth Muscle Cells (VSMCs) undergo reprogramming into osteoblast-like cells in response to calcium and phosphate mineral imbalance in CKD patients. This osteogenic switch is driven by the expression of several bone markers such as Runt- related transcription factor 2 (Runx2), Alkaline Phosphatase (ALP), Osteopontin (OPN), Matrix-Gla Protein (MGP), Osteocalcin (OCN), Type I Collagen (COL1), and Bone Sialo Proteins (BSPs). Recent studies showed that VSMCs secrete heterogeneous populations of Extracellular Vesicles (EVs)11 that are enriched under physiological conditions by calcification inhibitors such as Fetuin-A and MGP12,13,14. Interestingly, under pathological conditions, secreted EVs have a pro-calcifying profile and thereby act as nucleating foci for hydroxyapatite crystallization and propagation11,15. Electron Microscopy based studies revealed that EVs were embedded between collagen and elastin fibrils of arterial walls suggesting that calcification can be initiated through the EVs’ direct physical interaction with them13,16. We previously showed that a specific oligogalacturonic acid with a degree of polymerization of 8 (DP8) was able to inhibit vascular calcification. This inhibition was partly due to a decrease of osteogenic markers’s expression but also to the masking of a consensus sequence found in COL1 i.e. GFOGER sequence, thus preventing EVs from binding to COL1. Although the use of DP8 in-vivo seems to be compromised due to probable enzymatic digestion, these results suggested that the inhibition of VSMCs’ osteogenic switch and the prevention of EVs-COL1 interaction could represent new potential therapeutic targets for inhibiting VC17. Since we have already showed that the triple-helical GFOGER consensus sequence forms a preferential binding site for EVs17, we thereby chemically synthesized a GFOGER peptide in order to determine its ability to inhibit VC on VSMCs and on an aortic ring ex-vivo model. We also aim to decipher the mechanisms of inhibition by investigating the osteogenic markers’ expression as well as the protein content of secreted EVs in the presence of the GFOGER peptide.

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Vascular calcification is accelerated by hyponatremia and low osmolality condition via activating Rac1-Akt pathway

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