SENP1 protects cisplatin-induced AKI by attenuating apoptosis through regulation of HIF-1α
SENP1 protects cisplatin-induced AKI by attenuating apoptosis through regulation of HIF-1α
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DOI：
10.1016/j.yexcr.2022.113281
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发表时间：
2022-08-07
影响因子：
3.7
通讯作者：
Chen，Dongping
中科院分区：
文献类型：
--
作者：
Wang，Ling;Gao，Xiang;Chen，Dongping
背景急性肾损伤是一种发病率高、病死率高的临床综合征。然而，AKI的潜在分子机制在很大程度上仍不清楚。SENP1在急性肾损伤中的作用尚不清楚，其底物之一缺氧诱导因子-1α在急性肾损伤中具有肾脏保护作用。本研究从细胞模型和动物模型两个方面探讨了α轴在急性脑损伤中的作用。方法采用小鼠和HK-2细胞建立顺铂诱导的急性脑损伤模型，通过临床标本和顺铂诱导的急性脑损伤模型，研究脑缺血再灌注对细胞凋亡的影响。本实验在体内外研究了SENP1基因敲除或过表达对顺铂诱导的急性肾小管上皮细胞损伤的影响。在探讨急性脑损伤后缺氧诱导因子-1α表达变化的基础上，研究了SENP1基因敲除和HIF-1α过表达对急性脑损伤的协同作用。SENP1在HK-2细胞中的表达下调或过表达分别可通过调节细胞凋亡而促进或抑制AKI。与野生型小鼠相比，SENP1+/−小鼠发生的急性KI更为严重。此外，我们还发现，HIF-1α的过表达可以减弱SENP1基因敲除所致的急性肾损伤和促进细胞凋亡的作用。结论：SENP1通过调节细胞凋亡和调节HIF-1α，对急性肾损伤具有保护作用。本研究有助于了解AKI的发病机制，为AKI的治疗提供潜在的治疗靶点。
BackgroundAcute 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.MethodsWe 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 studiedin vitroandin 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.ResultsThe 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.Conclusions: we showed that SENP1 provided protection for kidney in AKIviaregulating 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.