Wen Xiaoyan, Li Shengnan, Frank Alicia, Chen Xiukai, Emlet David, Hukriede Neil A, Kellum John A
Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3347 Forbes Ave, Suite 220, Pittsburgh, PA, 15213, USA.
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Intensive Care Med Exp. 2020 Feb 7;8(1):9. doi: 10.1186/s40635-020-0297-3.
Sepsis, a dysregulated host response to infection with results in organ dysfunction, has been a major challenge to the development of effective therapeutics. Sepsis-associated acute kidney injury (S-AKI) results in a 3-5-fold increase in the risk of hospital mortality compared to sepsis alone. The development of therapies to reverse S-AKI could therefore significantly affect sepsis outcomes. However, the translation of therapies from preclinical studies into humans requires model systems that recapitulate clinical scenarios and the development of renal fibrosis indicative of the transition from acute to chronic kidney disease.
Here we characterized a murine model of S-AKI induced by abdominal sepsis developing into a chronic phenotype. We applied a small molecule histone deacetylase-8 inhibitor, UPHD186, and found that early treatment, beginning at 48 h post-sepsis, worsened renal outcome accompanied by decreasing mononuclear cell infiltration in the kidney, skewing cells into a pro-inflammatory phenotype, and increased pro-fibrotic gene expression, while delayed treatment, beginning at 96 h post-sepsis, after the acute inflammation in the kidney had subsided, resulted in improved survival and kidney histology presumably through promoting proliferation and inhibiting fibrosis.
These findings not only present a clinically relevant S-AKI model, but also introduce a timing dimension into S-AKI therapeutic interventions that delayed treatment with UPHD186 may enhance renal histologic repair. Our results provide novel insights into successful repair of kidney injury and sepsis therapy.
脓毒症是宿主对感染的失调反应，可导致器官功能障碍，一直是有效治疗方法开发面临的重大挑战。与单纯脓毒症相比，脓毒症相关的急性肾损伤（S-AKI）会使医院死亡率风险增加3至5倍。因此，开发逆转S-AKI的疗法可能会显著影响脓毒症的治疗结果。然而，将临床前研究中的疗法转化应用于人体需要能够重现临床情况的模型系统，以及能够体现从急性肾病向慢性肾病转变的肾纤维化模型。
在此，我们对由腹部脓毒症诱导发展为慢性表型的S-AKI小鼠模型进行了表征。我们应用了一种小分子组蛋白去乙酰化酶8抑制剂UPHD186，发现脓毒症后48小时开始的早期治疗会使肾脏结局恶化，同时伴有肾脏单核细胞浸润减少、细胞偏向促炎表型以及促纤维化基因表达增加，而在肾脏急性炎症消退后的脓毒症后96小时开始的延迟治疗，可能通过促进增殖和抑制纤维化，改善了生存率和肾脏组织学表现。
这些发现不仅提供了一个与临床相关的S-AKI模型，还为S-AKI治疗干预引入了一个时间维度，即延迟使用UPHD186治疗可能会增强肾脏组织学修复。我们的结果为肾脏损伤的成功修复和脓毒症治疗提供了新的见解。
