Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States.
Division of Anesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Am J Physiol Renal Physiol. 2024 Oct 1;327(4):F623-F636. doi: 10.1152/ajprenal.00132.2024. Epub 2024 Aug 8.
The chemotherapeutic agent cisplatin accumulates in the kidneys, leading to acute kidney injury (AKI). Preclinical and clinical studies have demonstrated sex-dependent outcomes of cisplatin-AKI. Deranged histone deacetylase (HDAC) activity is hypothesized to promote the pathogenesis of male murine cisplatin-AKI; however, it is unknown whether there are sex differences in the kidney HDACs. We hypothesized that there would be sex-specific expression, localization, or enzymatic activity, which may explain sexual dimorphic responses to cisplatin-AKI. In normal human kidney RNA samples, was significantly greater in the kidneys of women compared with men, whereas , , , and were differentially expressed between the kidney cortex and medulla, regardless of sex. In a murine model of cisplatin-AKI (3 days after a 15 mg/kg injection), we found few sex- or cisplatin-related differences in kidney transcripts among the mice. Although was significantly greater in female mice compared with male mice, HDAC9 protein localization did not differ. transcripts were greater in the inner medulla of cisplatin-AKI mice, regardless of sex, and this agreed with a greater HDAC7 abundance. HDAC activity within the cortex, outer medulla, and inner medulla was significantly lower in cisplatin-AKI mice but did not differ between the sexes. In agreement with these findings, a class I HDAC inhibitor did not improve kidney injury or function. In conclusion, even though cisplatin-AKI was evident and there were transcript level differences among the different kidney regions in this model, there were few sex- or cisplatin-dependent effects on kidney HDAC localization or activity. Kidney histone deacetylases (HDACs) are abundant in male and female mice, and the inner medulla has the greatest HDAC activity. A low dose of cisplatin caused acute kidney injury (AKI) in these mice, but there were few changes in kidney HDACs at the RNA/protein/activity level. A class I HDAC inhibitor failed to improve AKI outcomes. Defining the HDAC isoform, cellular source, and interventional timing is necessary to determine whether HDAC inhibition is a therapeutic strategy to prevent cisplatin-AKI in both sexes.
顺铂等化疗药物在肾脏中蓄积，导致急性肾损伤（AKI）。临床前和临床研究表明，顺铂致 AKI 的结果存在性别依赖性。有假说认为，组蛋白去乙酰化酶（HDAC）活性紊乱可促进雄性小鼠顺铂致 AKI 的发病机制；然而，尚不清楚肾脏 HDAC 是否存在性别差异。我们假设肾脏 HDAC 存在性别特异性表达、定位或酶活性，这可能解释了两性对顺铂致 AKI 反应的不同。在正常人类肾脏 RNA 样本中，女性肾脏中的 表达显著高于男性，而 、 、 、 无论性别如何，在肾脏皮质和髓质之间的表达均存在差异。在顺铂致 AKI 的小鼠模型中（顺铂注射后 3 天），我们发现，与性别或顺铂相关的 肾脏转录物在雌雄小鼠之间差异很小。尽管与雄性小鼠相比，雌性小鼠的 显著增加，但 HDAC9 蛋白定位没有差异。无论性别如何，顺铂致 AKI 小鼠的内髓质 转录物均增加，且与 HDAC7 丰度增加一致。皮质、外髓质和内髓质的 HDAC 活性在顺铂致 AKI 小鼠中显著降低，但雌雄之间没有差异。这些发现与一种 I 类 HDAC 抑制剂不能改善肾损伤或功能的结果一致。总之，尽管该模型中顺铂致 AKI 明显，不同肾脏区域的转录物水平存在差异，但肾脏 HDAC 定位或活性在性别或顺铂依赖性方面的差异很小。肾脏组蛋白去乙酰化酶（HDACs）在雄性和雌性小鼠中含量丰富，内髓质的 HDAC 活性最高。低剂量顺铂可导致这些小鼠发生急性肾损伤（AKI），但在 RNA/蛋白/活性水平上，肾脏 HDAC 几乎没有变化。I 类 HDAC 抑制剂未能改善 AKI 结局。明确 HDAC 同工型、细胞来源和干预时机对于确定 HDAC 抑制是否是预防两性顺铂致 AKI 的治疗策略是必要的。
