Department of Nephrology & Rheumatology, Shanghai Tenth People's Hospital of Tongji University, No. 301 YanChang Road, Shanghai, 200072, China.
Division of Nephrology, Kidney Institution of PLA, Chang Zheng Hospital, Second Military Medical University, No. 415 FengYang Road, Shanghai, 200003, China.
Exp Cell Res. 2022 Oct 1;419(1):113281. doi: 10.1016/j.yexcr.2022.113281. Epub 2022 Jul 15.
Acute kidney injury is a clinical syndrome with both high morbidity and mortality. However, the underlying molecular mechanism of AKI is still largely unknown. The role of SENP1 in AKI is unclear, while one of its substrates, HIF-1α possesses nephroprotective effect in AKI. Herein, this study aimed to reveal the role of SENP1/HIF-1α axis in AKI by using both cell and animal models.
We investigated the effects of AKI on SENP1 expression using clinical samples, and cisplatin-induced AKI model based on mice or HK-2 cells. The influence of SENP1 knockdown or over-expression on cisplatin-induced AKI was studied in vitro and in vivo. Following the exploration of the change in HIF-1α expression brought by AKI, the synergistic effects of SENP1 knockdown and HIF-1α over-expression on AKI were examined.
The results showed the up-regulation of SENP1 in clinical specimens, as well as cell and animal models. The knockdown or over-expression of SENP1 in HK-2 cells could promote or inhibit AKI through regulating cell apoptosis, respectively. Moreover, SENP1 mice suffered from much more serious AKI compared with mice in wild type group. Furthermore, we found that HIF-1α over-expression could attenuate the promoted cell apoptosis as well as AKI induced by SENP1 knockdown.
we showed that SENP1 provided protection for kidney in AKI via regulating cell apoptosis and through the regulation of HIF-1α. This study could benefit for the understanding of the pathogenesis of AKI and provide potential therapeutic target for AKI treatment.
急性肾损伤是一种具有高发病率和死亡率的临床综合征。然而，AKI 的潜在分子机制在很大程度上仍不清楚。SENP1 在 AKI 中的作用尚不清楚，而其底物之一 HIF-1α 在 AKI 中具有肾保护作用。在此，本研究旨在通过细胞和动物模型来揭示 SENP1/HIF-1α 轴在 AKI 中的作用。
我们使用临床样本研究了 AKI 对 SENP1 表达的影响，并基于小鼠或 HK-2 细胞建立了顺铂诱导的 AKI 模型。在体外和体内研究了 SENP1 敲低或过表达对顺铂诱导的 AKI 的影响。在探讨了 AKI 引起的 HIF-1α 表达变化后，研究了 SENP1 敲低和 HIF-1α 过表达对 AKI 的协同作用。
结果显示，临床标本以及细胞和动物模型中 SENP1 表达上调。HK-2 细胞中 SENP1 的敲低或过表达可分别通过调节细胞凋亡促进或抑制 AKI。此外，与野生型组相比，SENP1 敲除小鼠发生的 AKI 更为严重。此外，我们发现 HIF-1α 过表达可减轻 SENP1 敲低引起的促进细胞凋亡和 AKI。
我们表明，SENP1 通过调节细胞凋亡并通过调节 HIF-1α为 AKI 中的肾脏提供保护。本研究有助于了解 AKI 的发病机制，并为 AKI 的治疗提供潜在的治疗靶点。
