Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy.
Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy.
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SIRT2（沉默交配型信息调节 2 同源物-2）对 Septin4 的去乙酰化可减轻高血压肾病的损害
DOI：
10.1161/circresaha.122.321591
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发表时间：
2023-03-03
影响因子：
20.1
通讯作者：
Sun, Yingxian
中科院分区：
文献类型：
--
作者：
Zhang, Ying;Zhang, Naijin;Zou, Yuanming;Song, Chunyu;Cao, Kexin;Wu, Boquan;You, Shilong;Lu, Saien;Wang, Dong;Xu, Jiaqi;Huang, Xinyue;Zhang, Pengyu;Fan, Zihao;Liu, Jingwei;Cheng, Zhongyi;Zhang, Zhe;Kong, Chuize;Cao, Liu;Sun, Yingxian
背景：高血压可导致足细胞损伤和随后的细胞凋亡，最终导致肾小球硬化。虽然减轻足细胞凋亡对高血压肾病的治疗具有临床意义，但有效的治疗靶点尚未确定。septin4是一种促凋亡蛋白，是器官损伤的重要标志，其功能受翻译后修饰的调节。然而，septin4在调节足细胞凋亡中的确切作用及其与高血压肾损害的关系尚不清楚。方法：探讨septin4在高血压肾病中的作用及机制，为针对性治疗高血压肾病提供理论依据。采用Rosa 26 (Gt(Rosa)26Sor)-SIRT2（沉默配对型信息调节2同源物-2）-Flag-TG（转基因）（SIRT2-TG）小鼠sirt2敲除小鼠和septin4-K174Q突变小鼠模型，结合蛋白质组学和乙酰蛋白质组学分析，随后采用多种分子生物学方法，验证了sirt2介导的高血压肾病中septin4-K174去乙酰化的机制。结果：用抗氧化剂Tempol处理转基因septin4- k174q突变小鼠，我们发现septin4 K174位点的高乙酰化加剧了Ang II（血管紧张素II）诱导的氧化应激引起的高血压肾损伤。蛋白质组学和Western blotting分析表明，septin4-K174Q激活了裂解- parp1（聚[adp核糖]聚合酶家族，成员1）-裂解-caspase3途径。在septin4敲低的人肾足细胞中，septin4-K174R模拟K174的去乙酰化，挽救了Ang II诱导的足细胞凋亡。免疫沉淀和质谱分析鉴定SIRT2是一种去乙酰化酶，它与septin4 GTPase结构域相互作用，使septin4- k174去乙酰化。在sirt2缺陷小鼠和sirt2敲低的肾足细胞中，septin4-K174保持高乙酰化并加剧高血压性肾损伤。相反，在Rosa26-Sirt2-Flag （SIRT2- tg）小鼠和SIRT2敲低再表达野生型SIRT2的肾足细胞中，septin4-K174被低乙酰化并减轻高血压肾损伤。结论：通过K174 （K174Q）乙酰化激活的Septin4可促进高血压肾损伤。Septin4-K174R模拟SIRT2的去乙酰化，抑制裂解- parp1 -裂解-caspase3通路。Septin4-K174R作为肾保护因子，可减轻angii诱导的高血压肾损伤。这些结果表明，septin4-K174是治疗高血压肾损伤的潜在靶点。
Background: Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of septin4, a proapoptotic protein and an important marker of organ damage, is regulated by post-translational modification. However, the exact role of septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear. Methods: We investigated the function and mechanism of septin4 in hypertensive nephropathy to discover a theoretical basis for targeted treatment. Mouse models including Rosa 26 (Gt(ROSA)26Sor)-SIRT2 (silent mating type information regulation 2 homolog-2)-Flag-TG (transgenic) (SIRT2-TG) mice SIRT2-knockout, and septin4-K174Q mutant mice, combined with proteomic and acetyl proteomics analysis, followed by multiple molecular biological methodologies, were used to demonstrate mechanisms of SIRT2-mediated deacetylation of septin4-K174 in hypertensive nephropathy. Results: Using transgenic septin4-K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of septin4 exacerbates Ang II (angiotensin II)– induced hypertensive renal injury resulting from oxidative stress. Proteomics and Western blotting assays indicated that septin4-K174Q activates the cleaved-PARP1 (poly [ADP-ribose] polymerase family, member 1)-cleaved-caspase3 pathway. In septin4-knockdown human renal podocytes, septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by Ang II. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the septin4 GTPase domain and deacetylates septin4-K174. In Sirt2-deficient mice and SIRT2-knockdown renal podocytes, septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes reexpressing wild-type SIRT2, septin4-K174 is hypoacetylated and mitigates hypertensive renal injury. Conclusions: Septin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating Ang II–induced hypertensive renal injury. These findings indicate that septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.
吡喹酮治疗后日本血吸虫感染小鼠肝脏中Septin4的表达
影响因子：
3.2
作者：
Zhu D;Song K;Chen J;Wang J;Sun X;Qian H;Gu X;Zhang L;Qin Y;Duan Y
通讯作者：
Duan Y