Alkhaleq Heba Abd, Hacker Israel, Karram Tony, Hamoud Shadi, Kabala Aviva, Abassi Zaid
Department of Physiology and Biophysics, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Department of Vascular Surgery, Rambam Health Care Campus, Haifa 3109601, Israel.
Biomedicines. 2024 Oct 12;12(10):2323. doi: 10.3390/biomedicines12102323.
The incidence of acute kidney injury (AKI) has been steadily increasing. Despite its high prevalence, there is no pathogenetically rational therapy for AKI. This deficiency stems from the poor understanding of the pathogenesis of AKI. Renal ischemia/hypoxia is one of the leading causes of clinical AKI. This study investigates whether αMUPA mice, overexpressing the urokinase plasminogen activator (uPA) gene are protected against ischemic AKI, thus unraveling a potential renal damage treatment target. We utilized an in vivo model of I/R-induced AKI in αMUPA mice and in vitro experiments of uPA-treated HEK-293 cells. We evaluated renal injury markers, histological changes, mRNA expression of inflammatory, apoptotic, and autophagy markers, as compared with wild-type animals. the αMUPA mice exhibited less renal injury post-AKI, as was evident by lower SCr, BUN, and renal NGAL and KIM-1 along attenuated adverse histological alterations. Notably, the αMUPA mice exhibited decreased levels pro-inflammatory, fibrotic, apoptotic, and autophagy markers like TGF-β, IL-6, STAT3, IKB, MAPK, Caspase-3, and LC3. By contrast, ACE-2, p-eNOS, and PGC1α were higher in the kidneys of the αMUPA mice. In vitro results of the uPA-treated HEK-293 cells mirrored the in vivo findings. These results indicate that uPA modulates key pathways involved in AKI, offering potential therapeutic targets for mitigating renal damage.
急性肾损伤（AKI）的发病率一直在稳步上升。尽管其患病率很高，但目前尚无针对AKI的基于发病机制的合理治疗方法。这种不足源于对AKI发病机制的了解不足。肾缺血/缺氧是临床AKI的主要原因之一。本研究调查了过表达尿激酶型纤溶酶原激活剂（uPA）基因的αMUPA小鼠是否对缺血性AKI具有保护作用，从而揭示一个潜在的肾损伤治疗靶点。我们在αMUPA小鼠中使用了I/R诱导的AKI体内模型，并对uPA处理的HEK-293细胞进行了体外实验。与野生型动物相比，我们评估了肾损伤标志物、组织学变化、炎症、凋亡和自噬标志物的mRNA表达。αMUPA小鼠在AKI后表现出较少的肾损伤，较低的血清肌酐（SCr）、血尿素氮（BUN）以及肾中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和肾损伤分子-1（KIM-1）水平以及减轻的不良组织学改变均证明了这一点。值得注意的是，αMUPA小鼠中促炎、纤维化、凋亡和自噬标志物如转化生长因子-β（TGF-β）、白细胞介素-6（IL-6）、信号转导和转录激活因子3（STAT3）、核因子κB抑制蛋白（IKB）、丝裂原活化蛋白激酶（MAPK）、半胱天冬酶-3（Caspase-3）和微管相关蛋白1轻链3（LC3）的水平降低。相比之下，αMUPA小鼠肾脏中的血管紧张素转换酶2（ACE-2）、磷酸化内皮型一氧化氮合酶（p-eNOS）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）水平较高。uPA处理的HEK-293细胞的体外实验结果与体内研究结果一致。这些结果表明，uPA调节参与AKI的关键通路，为减轻肾损伤提供了潜在的治疗靶点。
