Vitamin K3 Analog Phthiocol Protects Against High Phosphate-Induced Vascular Calcification in Chronic Kidney Disease

TL;DR

A vitamin K3 analog called phthiocol helps prevent vascular calcification in chronic kidney disease by reducing cell death and oxidative stress.

Contribution

Phthiocol is shown to protect against high phosphate-induced vascular calcification via the PI3K/Akt and Nrf2/HO-1 pathways in a mouse model of CKD.

Findings

Phthiocol reduced reactive oxygen species and calcification in vascular smooth muscle cells.

Phthiocol improved dyslipidemia, hyperphosphatemia, and aortic stiffness in CKD mice.

Phthiocol inhibited osteogenic trans-differentiation by restoring PI3K/Akt and activating Nrf2/HO-1 signaling.

Abstract

Vascular calcification (VC) is a multifactorial pathological deposition of calcium in the vasculature and is associated with severe cardiovascular outcomes, particularly in patients with chronic kidney disease (CKD). Various vitamin K analogs have been found to influence the development of VC. We utilized a high-phosphate-induced VC model in mouse vascular smooth muscle cells (VSMCs) and developed an in vivo VC model using ApoE−/− mice subjected to 5/6 nephrectomy and fed an oral high-phosphorus diet to evaluate the effect of the vitamin K3 analog phthiocol. Transdermal glomerular filtration rate measurement, pulse wave velocity for aortic stiffness assessment, blood biochemical analysis, and pathological examinations were conducted. Phthiocol suppressed reactive oxygen species production and reduced subsequent cell death and calcification in a dose-dependent manner. It inhibited osteogenic trans-differentiation by restoring the PI3K/Akt pathway, activating Nrf2/HO-1 antioxidation signaling, and downregulating IL-1β and TNF-α. The high-phosphate diet in ApoE−/− CKD mice significantly induced dyslipidemia, renal impairment, hyperphosphatemia, aortic stiffness, and calcium deposition in aortic tissue compared to the control group. Phthiocol treatment markedly improved dyslipidemia, hyperphosphatemia, and aortic stiffness. The vitamin K3 analog phthiocol ameliorates phosphate-induced osteogenic trans-differentiation of VSMCs and subsequent VC by restoring the PI3K/Akt pathway and enhancing Nrf2/HO-1 antioxidant activity.

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