Sepsis-induced acute kidney injury (SA-AKI) is associated with high mortality rates, but clinicians lack effective treatments except supportive care or renal replacement therapies. Recently, histone deacetylase (HDAC) inhibitors have been recognized as potential treatments for AKI and sepsis in animal models; however, the adverse effect generated by use of pan-inhibitors of HDACs may limit their application in people. In this study, we explored the possible renoprotective effect of a selective class IIa HDAC inhibitor TMP195 in a murine model of SA-AKI induced by lipopolysaccharide (LPS). Administration of TMP195 significantly reduced increased serum creatinine and blood urea nitrogen levels and renal damage induced by LPS; this was coincident with reduced expression of HDAC4, a major isoform of class IIa HDACs, and elevated histone H3 acetylation. TMP195 treatment following LPS exposure also reduced renal tubular cell apoptosis and attenuated renal expression of NGAL and Kim-1, two biomarkers of tubular injury. Moreover, LPS exposure resulted in increased expression of BAX and cleaved caspase3, and decreased expression of BCL-2 and BMP-7 in vivo and in vitro; TMP195 treatment reversed these responses. Finally, TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including ICAM-1, MCP-1, TNF-α, and IL-1β and accumulation of inflammatory cells in the injured kidney. Collectively, these data indicated that TMP195 has a powerful renoprotective effect in SA-AKI by mitigating renal tubular cell apoptosis and inflammation, and suggest that targeting class IIa HDACs might be a novel therapeutic strategy for the treatment of SA-AKI that avoids the unintended adverse effects of a pan-HDAC inhibitor.

中文翻译：

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IIa类HDAC抑制剂TMP195减轻脂多糖诱导的急性肾损伤

脓毒症引起的急性肾损伤 (SA-AKI) 与高死亡率相关，但临床医生除了支持治疗或肾脏替代疗法外缺乏有效的治疗方法。最近，组蛋白去乙酰化酶 (HDAC) 抑制剂已被公认为动物模型中 AKI 和败血症的潜在治疗方法。然而，使用 HDAC 的泛抑制剂产生的不利影响可能会限制其在人体中的应用。在这项研究中，我们探讨了选择性 IIa 类 HDAC 抑制剂 TMP195 在脂多糖 (LPS) 诱导的 SA-AKI 小鼠模型中可能的肾脏保护作用。TMP195 的给药显着降低了 LPS 引起的血清肌酐和血尿素氮水平升高以及肾损伤；这与 HDAC4（IIa 类 HDAC 的主要同种型）的表达降低和组蛋白 H3 乙酰化升高相一致。LPS 暴露后的 TMP195 治疗也减少了肾小管细胞凋亡并减弱了肾小管损伤的两种生物标志物 NGAL 和 Kim-1 的表达。此外，LPS 暴露导致体内和体外 BAX 和裂解的 caspase3 表达增加，BCL-2 和 BMP-7 表达降低；TMP195 治疗逆转了这些反应。最后，TMP195 抑制 LPS 诱导的多种促炎细胞因子/趋化因子的上调，包括 ICAM-1、MCP-1、TNF-α 和 IL-1β，以及受损肾脏中炎症细胞的积累。总的来说，这些数据表明 TMP195 通过减轻肾小管细胞凋亡和炎症，在 SA-AKI 中具有强大的肾脏保护作用，