He Yanqiu, Xie Yumei, Zhou Tingting, Li Dongze, Cheng Xi, Yang Ping, Luo Changfang, Liu Yijun, Guo Man, Wan Qin, Yan Pijun, Gao Chenlin, Zhang Yuan-Yuan, Sun Xiao-Dong, Xu Yong, Huang Wei
Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, China.
Inflammation. 2025 Feb;48(1):254-275. doi: 10.1007/s10753-024-02047-w. Epub 2024 Jun 1.
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, inflammation and fibrosis play an important role in its progression. Histone lysine crotonylation (Kcr) was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of sodium crotonate (NaCr) and histone Kcr in kidney diseases. However, the effects of NaCr and NaCr-induced Kcr on DKD remain unclear. In this study, db/db mice and high glucose-induced human tubular epithelial cells (HK-2) were used respectively, and exogenous NaCr and crotonoyl-coenzyme A (Cr-CoA) as intervention reagents, histone Kcr and DKD-related indicators were detected. The results confirmed that NaCr had an antidiabetic effect and decreased blood glucose and serum lipid levels and alleviated renal function and DKD-related inflammatory and fibrotic damage. NaCr also induced histone Kcr and histone H3K18 crotonylation (H3K18cr). However, NaCr and Cr-CoA-induced histone Kcr and protective effects were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300 in vitro. In summary, our data reveal that NaCr may mitigate DKD via an antidiabetic effect as well as through ACSS2 and P300-induced histone Kcr, suggesting that Kcr may be the potential molecular mechanism and prevention target of DKD.
糖尿病肾病（DKD）是糖尿病常见的微血管并发症，炎症和纤维化在其进展中起重要作用。组蛋白赖氨酸巴豆酰化（Kcr）于2011年首次被鉴定为一种新型的翻译后修饰。近年来，巴豆酸钠（NaCr）和组蛋白Kcr在肾脏疾病研究方面取得了显著进展。然而，NaCr和NaCr诱导的Kcr对DKD的影响仍不清楚。在本研究中，分别使用db/db小鼠和高糖诱导的人肾小管上皮细胞（HK-2），并以外源NaCr和巴豆酰辅酶A（Cr-CoA）作为干预试剂，检测组蛋白Kcr和DKD相关指标。结果证实，NaCr具有抗糖尿病作用，可降低血糖和血脂水平，减轻肾功能以及DKD相关的炎症和纤维化损伤。NaCr还诱导组蛋白Kcr和组蛋白H3K18巴豆酰化（H3K18cr）。然而，在体外抑制酰基辅酶A合成酶短链家族成员2（ACSS2）或组蛋白酰基转移酶P300的活性可逆转NaCr和Cr-CoA诱导的组蛋白Kcr及保护作用。总之，我们的数据表明，NaCr可能通过抗糖尿病作用以及ACSS2和P300诱导的组蛋白Kcr减轻DKD，提示Kcr可能是DKD潜在的分子机制和预防靶点。
