Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Second Xiangya Hospital at Central South University, Changsha, Hunan, China.
Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Second Xiangya Hospital at Central South University, Changsha, Hunan, China.
Kidney Int. 2020 Jan;97(1):106-118. doi: 10.1016/j.kint.2019.08.028. Epub 2019 Sep 17.
Fibrosis is a common pathologic pathway of progressive kidney disease involving complex signaling networks. The deacetylase sirtuin 6 (sirt6) was recently implicated in kidney injury. However, it remains elusive whether and how sirt6 contributes to the regulation of kidney fibrosis. Here, we demonstrate that sirt6 protects against kidney interstitial fibrosis through epigenetic regulation of β-catenin signaling. Sirt6 is markedly upregulated during fibrogenesis following obstructed nephropathy and kidney ischemia-reperfusion injury. Pharmacological inhibition of sirt6 deacetylase activity aggravates kidney fibrosis in obstructed nephropathy. Consistently, knockdown of sirt6 in mouse kidney proximal tubular epithelial cells aggravates transforming growth factor-β-induced fibrosis in vitro. Mechanistically, sirt6 deficiency results in augmented expression of the downstream target proteins of β-catenin signaling. We further show that sirt6 interacts with β-catenin during transforming growth factor-β treatment and binds to the promoters of β-catenin target genes, resulting in the deacetylation of histone H3K56 to prevent the transcription of fibrosis-related genes. Thus, our data reveal the anti-fibrotic function of sirt6 by epigenetically attenuating β-catenin target gene expression.
纤维化是一种涉及复杂信号网络的进行性肾脏疾病的常见病理途径。去乙酰化酶 Sirtuin 6（Sirt6）最近被牵连到肾脏损伤中。然而，Sirt6 是否以及如何参与肾脏纤维化的调节仍然难以捉摸。在这里，我们证明 Sirt6 通过β-catenin 信号的表观遗传调控来防止肾脏间质纤维化。在梗阻性肾病和肾缺血再灌注损伤后的纤维化过程中，Sirt6 明显上调。抑制 Sirt6 去乙酰化酶活性会加重梗阻性肾病中的肾脏纤维化。一致地，在小鼠肾脏近端肾小管上皮细胞中敲低 Sirt6 会加重体外转化生长因子-β诱导的纤维化。在机制上，Sirt6 缺乏会导致β-catenin 信号的下游靶蛋白表达增加。我们进一步表明，Sirt6 在转化生长因子-β处理期间与β-catenin 相互作用，并结合β-catenin 靶基因的启动子，导致组蛋白 H3K56 的去乙酰化，从而阻止纤维化相关基因的转录。因此，我们的数据揭示了 Sirt6 通过表观遗传减弱β-catenin 靶基因表达来发挥抗纤维化功能。
