Global Analysis of the Acetylome in Cisplatin-Induced Renal Fibrosis in C57BL/6 Mice

Background: Chronic kidney disease (CKD)
is a major
global health burden, and progressive renal fibrosis is a common end-stage
pathway to renal failure. Lysine acetylation, as an important post-translational
modification, has gradually become a reversible regulatory factor
in renal injury and repair, but its systemic role in cisplatin-induced
renal fibrosis remains unclear. Methods: Label-free quantitative
proteomics and acetylome analyses were performed on the kidneys of
C57BL/6 mice with cisplatin-induced renal fibrosis as well as the
control groups (n = 4 per group). Subsequently, we
conducted comprehensive bioinformatics analyses to identify key molecules
that promote renal fibrosis. Results: We established
proteomic and acetylomic profiles of lesions caused by cisplatin-induced
renal fibrosis. Cisplatin-induced injury triggered extensive Kac remodeling,
primarily involving pathways, such as the cell cycle, ATP-dependent
chromatin remodeling, cell death, and extracellular matrix receptor
interactions. We also identified significantly elevated lysine-96
acetylation of histone H2A (H2ac4 K96ac), whose abundance positively
correlated to that of the acetyltransferase p300. This suggests that
H2ac4 K96ac is a candidate epigenetic marker associated with cisplatin-induced
renal fibrosis and warrants further investigation. Conclusion: This study provides comprehensive proteomic and acetylated proteomic
data sets and maps for cisplatin-induced renal fibrosis. It is speculated
that the H2ac4 K96ac histone acetylation site may represent a novel
therapeutic target.

背景：慢性肾脏病（Chronic kidney disease, CKD）是全球性重大健康负担，而进行性肾纤维化是肾衰竭常见的终末期病理通路。赖氨酸乙酰化（lysine acetylation）作为一类重要的翻译后修饰（post-translational modification），已逐渐成为肾损伤与修复过程中的可逆调控因子，但其在顺铂诱导的肾纤维化中的系统性作用仍未明确。
方法：本研究对顺铂诱导肾纤维化的C57BL/6小鼠肾脏及对照组（每组n=4）开展无标记定量蛋白质组学（Label-free quantitative proteomics）与乙酰化修饰组学（acetylome）分析。随后通过全面的生物信息学分析，筛选出促进肾纤维化的关键分子。
结果：本研究构建了顺铂诱导肾纤维化所致损伤的蛋白质组与乙酰化修饰组图谱。顺铂诱导的肾损伤引发了广泛的赖氨酸乙酰化（Kac）重塑，主要涉及细胞周期、ATP依赖型染色质重塑、细胞死亡及细胞外基质受体相互作用等通路。此外，本研究还发现组蛋白H2A的赖氨酸96乙酰化位点（H2ac4 K96ac）水平显著升高，其丰度与乙酰转移酶p300的表达量呈正相关。这提示H2ac4 K96ac是与顺铂诱导肾纤维化相关的候选表观遗传标志物，有待进一步研究验证。
结论：本研究提供了顺铂诱导肾纤维化的完整蛋白质组与乙酰化蛋白质组数据集及图谱。推测H2ac4 K96ac组蛋白乙酰化位点或可成为新型治疗靶点。