Datta Aishika, Patale Priti, Ghosh Debarati, Jagtap Priya, Shah Jinagna, Katamneni Mounika, Kumari Anita, Malik Nikita, Karmarkar Gautam, Barik Anirban, Ghosh Bijoyani, Dhakne Pooja, Pathulothu Vinod, Sarmah Deepaneeta, Kaur Harpreet, Rana Nikita, Rathod Rajeshwari, Borah Anupom, Sengupta Pinaki, Bhattacharya Pallab
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India.
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India.
Commun Biol. 2025 Apr 29;8(1):677. doi: 10.1038/s42003-025-08100-0.
Stroke is one of the major causes of mortality and long-term disability worldwide. Chronic-kidney-disease (CKD) is a condition where patients have shown increased vulnerability to stroke with poor functional and cognitive outcomes. Impaired cerebral autoregulation in CKD patients may impose a high risk of stroke. To date, the mechanism of worsened stroke outcomes in CKD patients are limitedly understood. Alterations of endoplasmic-reticulum (ER) homoeostasis via modification of Sel1L-Hrd1 complex is one of the many cellular events that gets triggered following both CKD and stroke leading to accumulation of misfolded proteins, culminating in ER-stress. Therefore, the present study aims to explore the involvement of Sel1L mediated altered ER functions towards worsening of stroke outcome in CKD and further its crucial role towards white matter damage. CKD-stroke complex was induced in male Sprague-Dawley rats followed by middle-cerebral-artery occlusion. At 24 h and 7 day of reperfusion, animals were subjected to behavioral analysis followed by euthanasia, brain harvest and molecular studies. CKD-Stroke-complex animals showed aggravated neurofunctional and cognitive impairment which were further normalized by treatment of an ER-stress inhibitor. This indicates exacerbated stroke outcome in CKD-stroke-complex may be mediated by imbalanced ER-homeostasis due to decreased Sel1L expression leading to enhanced cellular death and neurodegeneration.
中风是全球范围内导致死亡和长期残疾的主要原因之一。慢性肾脏病（CKD）是一种患者对中风易感性增加且功能和认知预后较差的疾病。CKD患者的脑自动调节功能受损可能会带来较高的中风风险。迄今为止，对CKD患者中风预后恶化的机制了解有限。通过修饰Sel1L-Hrd1复合物来改变内质网（ER）稳态是CKD和中风后引发的众多细胞事件之一，会导致错误折叠蛋白的积累，最终引发内质网应激。因此，本研究旨在探讨Sel1L介导的内质网功能改变对CKD患者中风预后恶化的影响，以及其对白质损伤的关键作用。在雄性Sprague-Dawley大鼠中诱导建立CKD-中风复合体模型，随后进行大脑中动脉闭塞。在再灌注24小时和7天时，对动物进行行为分析，然后实施安乐死、取脑并进行分子研究。CKD-中风复合体动物表现出神经功能和认知障碍加重，而内质网应激抑制剂治疗可使其恢复正常。这表明CKD-中风复合体中中风预后恶化可能是由于Sel1L表达降低导致内质网稳态失衡，进而导致细胞死亡增加和神经退行性变所致。
