SIRT6 overexpression retards renal interstitial fibrosis through targeting HIPK2 in chronic kidney disease.
SIRT6 overexpression retards renal interstitial fibrosis through targeting HIPK2 in chronic kidney disease.
复制标题
SIRT6 过表达通过靶向 HIPK2 在慢性肾脏病中延缓肾间质纤维化
DOI：
10.3389/fphar.2022.1007168
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
肾间质纤维化是慢性肾病（CKD）中一种常见的病理生理改变。烟酰胺腺嘌呤二核苷酸（NAD）依赖的去乙酰化酶sirtuin 6 （SIRT6）被证明对肾损伤有保护作用。维生素B3是NAD前体最常用的形式。然而，SIRT6过表达在CKD肾间质纤维化中的作用以及饮食中维生素B3摄入量与肾功能之间的关系仍有待阐明。方法：给野生型（WT）和sirt6 -转基因（SIRT6-Tg）小鼠高腺嘌呤日粮建立CKD模型。将HK2细胞体外暴露于转化生长因子β1 （TGF-β1）中，探讨其作用机制。来自多民族动脉粥样硬化研究（MESA）的人群数据被用来研究膳食维生素B3摄入量与肾功能下降之间的关系。结果：与WT小鼠相比，SIRT6-Tg小鼠肾间质纤维化减轻，表现为胶原沉积、I型胶原和α-平滑肌肌动蛋白表达减少。SIRT6-Tg小鼠的肾功能也得到改善。同源结构域相互作用蛋白激酶2 （HIPK2）在CKD的纤维化过程中被诱导，而SIRT6过表达后HIPK2被下调。进一步的体外实验证实SIRT6缺失加剧了HK2细胞的上皮向间质转化，这可能与HIPK2上调有关。SIRT6在转录后水平抑制HIPK2。人群研究表明，在随访期间，≥65岁的人群中，较高的膳食维生素B3摄入量与较低的肾小球滤过率下降风险独立相关。结论：SIRT6/HIPK2轴是CKD肾间质纤维化的一个有希望的靶点。膳食中维生素B3的摄入有利于老年人的肾功能。
Introduction: Renal interstitial fibrosis is a common pathophysiological change in the chronic kidney disease (CKD). Nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin 6 (SIRT6) is demonstrated to protect against kidney injury. Vitamin B3 is the mostly used form of NAD precursors. However, the role of SIRT6 overexpression in renal interstitial fibrosis of CKD and the association between dietary vitamin B3 intake and renal function remain to be elucidated. Methods: Wild-type (WT) and SIRT6-transgene (SIRT6-Tg) mice were given with high-adenine diets to establish CKD model. HK2 cells were exposed to transforming growth factor β1 (TGF-β1) in vitro to explore related mechanism. Population data from Multi-Ethnic Study of Atherosclerosis (MESA) was used to examine the association between dietary vitamin B3 intake and renal function decline. Results: Compared to WT mice, SIRT6-Tg mice exhibited alleviated renal interstitial fibrosis as evidenced by reduced collagen deposit, collagen I and α-smooth muscle actin expression. Renal function was also improved in SIRT6-Tg mice. Homeodomain interacting protein kinase 2 (HIPK2) was induced during the fibrogenesis in CKD, while HIPK2 was downregulated after SIRT6 overexpression. Further assay in vitro confirmed that SIRT6 depletion exacerbated epithelial-to-mesenchymal transition of HK2 cells, which might be linked with HIPK2 upregulation. HIPK2 was inhibited by SIRT6 in the post-transcriptional level. Population study indicated that higher dietary vitamin B3 intake was independently correlated with a lower risk of estimate glomerular filtration rate decline in those ≥65 years old during follow-up. Conclusion: SIRT6/HIPK2 axis serves as a promising target of renal interstitial fibrosis in CKD. Dietary vitamin B3 intake is beneficial for renal function in the old people.
登录
查看更多内容
影响因子：
6
作者：
Jin, Jixiu;Li, Wenjia;Wang, Tian;Park, Byung-Hyun;Park, Sung Kwang;Kang, Kyung Pyo
通讯作者：
Kang, Kyung Pyo
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1073/pnas.1718819115
发表时间：
2018-02-20
影响因子：
11.1
作者：
Hou, Yujun;Lautrup, Sofie;Bohr, Vilhelm A.
通讯作者：
Bohr, Vilhelm A.
影响因子：
7.1
作者：
Dollerup, Ole L.;Christensen, Britt;Jessen, Niels
通讯作者：
Jessen, Niels
影响因子：
16
作者：
de la Vega, Laureano;Grishina, Irina;Schmitz, M. Lienhard
通讯作者：
Schmitz, M. Lienhard