A molecular target of vascular calcification in chronic kidney disease
Mohamed G. Atta
Mohamed G. Atta
Published January 4, 2022
Citation Information: J Clin Invest. 2022;132(1):e156257. https://doi.org/10.1172/JCI156257.
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Commentary

A molecular target of vascular calcification in chronic kidney disease

Abstract

Vascular calcification (VC) causes cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), particularly those with end-stage kidney disease (ESKD) on maintenance dialysis treatment. Although many mechanisms have been proposed, their detailed effects remain incompletely understood. In this issue of the JCI, Li et al. examined the molecular mechanism of the protective role of SIRT6 in VC in patients with CKD. Using in vitro and animal models of CKD, the authors demonstrated that SIRT6 prevents VC by suppressing the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Mechanistically, SIRT6 bound and deacetylated the runt-related transcription factor 2 (Runx2), a key transcription factor for osteogenic differentiation, promoting its nuclear export for proteasome degradation. These studies provide a pathway in the pathogenesis of VC and justify investigating SIRT6 as a potential target in CKD.

Authors

Mohamed G. Atta

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Figure 1

Mechanism for osteogenic transdifferentiation of VSMCs in the pathogenesis of VC.

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Mechanism for osteogenic transdifferentiation of VSMCs in the pathogenes...
VSMCs uptake phosphorus via the sodium-dependent phosphate cotransporters PiT-1 and PiT-2 in response to increases in extracellular phosphorus of any cause, most commonly in patients with CKD. This uptake leads to downregulation of SIRT6 expression, upregulation of bone morphogenic genes, and an increase in the expression of the transcription factor Runx2, the master regulator of bone formation. In the absence of SIRT6, Runx2 signals osteoblast maturation and matrix mineralization. In contrast, overexpression of SIRT6 marks Runx2 protein for ubiquitination and degradation, preventing VSMC calcification. The study by Li et al. (16) showed that SIRT6 upregulation in an environment of increased extracellular phosphorus leads to SIRT6 binding and deacetylation of Runx2 protein in VSMCs, promoting its nuclear export for proteasome degradation and thus preventing its downstream signal for osteogenic transdifferentiation.