SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease
Wenxin Li, … , Baohua Liu, Hui Huang
Wenxin Li, … , Baohua Liu, Hui Huang
Published November 18, 2021
Citation Information: J Clin Invest. 2022;132(1):e150051. https://doi.org/10.1172/JCI150051.
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Research Article Cell biology Vascular biology

SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease

Abstract

Vascular calcification (VC) is regarded as an important pathological change lacking effective treatment and associated with high mortality. Sirtuin 6 (SIRT6) is a member of the Sirtuin family, a class III histone deacetylase and a key epigenetic regulator. SIRT6 has a protective role in patients with chronic kidney disease (CKD). However, the exact role and molecular mechanism of SIRT6 in VC in patients with CKD remain unclear. Here, we demonstrated that SIRT6 was markedly downregulated in peripheral blood mononuclear cells (PBMCs) and in the radial artery tissue of patients with CKD with VC. SIRT6-transgenic (SIRT6-Tg) mice showed alleviated VC, while vascular smooth muscle cell–specific (VSMC-specific) SIRT6 knocked-down mice showed severe VC in CKD. SIRT6 suppressed the osteogenic transdifferentiation of VSMCs via regulation of runt-related transcription factor 2 (Runx2). Coimmunoprecipitation (co-IP) and immunoprecipitation (IP) assays confirmed that SIRT6 bound to Runx2. Moreover, Runx2 was deacetylated by SIRT6 and further promoted nuclear export via exportin 1 (XPO1), which in turn caused degradation of Runx2 through the ubiquitin-proteasome system. These results demonstrated that SIRT6 prevented VC by suppressing the osteogenic transdifferentiation of VSMCs, and as such targeting SIRT6 may be an appealing therapeutic target for VC in CKD.

Authors

Wenxin Li, Weijing Feng, Xiaoyan Su, Dongling Luo, Zhibing Li, Yongqiao Zhou, Yongjun Zhu, Mengbi Zhang, Jie Chen, Baohua Liu, Hui Huang

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Figure 2

SIRT6 attenuated VC.

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SIRT6 attenuated VC. (A) Computed tomography (CT) images showing calcifi...
(A) Computed tomography (CT) images showing calcification in the abdominal aorta. The green arrows and circle indicated the calcification in abdominal aorta of the WT mouse (n = 12 per group). The bar chart shows the relative VC Agatston score (fold change) of mouse aortas. Scale bars: 10 mm. (B) Representative von Kossa staining of abdominal aorta sections (n = 12 per group). Scale bars: 100 μm. (C) Western blot shows SIRT6 protein in abdominal aorta was reduced in VC. (D and E) VSMCs were exposed to Pi (3.0 mM) for 7 days and then stained for mineralization by Alizarin red (D), and the quantitative analysis of calcium content (E) and ALP (F) were detected (n = 3 per group). (G) SIRT6 protein expression was reduced in WT and SIRT6-Tg VSMCs in response to Pi (3.0 mM) treatment (n = 4 per group). (H–J) WT and SIRT6-Tg VSMCs were pretransfected with siSIRT6 or si-negative control (siNC) and then exposed to Pi (3.0 mM) for 7 days. VSMCs were stained for mineralization by Alizarin red S (H), and calcium content (I) and ALP (J) were quantified (n = 3 per group). Statistical significance was assessed using 1-way ANOVA followed by Dunnett’s test (A, C–F, I, and J). *P < 0.05. All values are mean ± SD.