Kaur Harpreet, Pandey Nilesh, Chandaluri Lakshmi, Shaaban Nirvana, Martinez Alexa, Kidder Evan, Patel Vishal J, Kshirsagar Samadhan G, Kumar Dhananjay, Frausto Louise, Pandit Rajan, Richard Koral S E, Anand Sumit Kumar, Das Sandeep, Vikram Ajit, Magdy Tarek, Lu Xiao-Hong, Orr A Wayne, Patel Harilal, Trivedi Ravi Kumar, Kansagra Kevinkumar, Joharapurkar Amit A, Parmar Deven V, Jain Mukul R, Rom Oren, Yurdagul Arif, Dhanesha Nirav
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Sarkhej Bavla NH 8A, Moraiya, Ahmedabad 382210, India.
Exp Neurol. 2025 Apr;386:115181. doi: 10.1016/j.expneurol.2025.115181. Epub 2025 Feb 4.
Patients with chronic kidney disease (CKD) are at a significantly increased risk of stroke and experience worse stroke outcomes and higher mortality. CKD exacerbates stroke risk and severity through a complex interplay of systemic inflammation, oxidative stress, and impaired clearance of uremic toxins, leading to neuroinflammation and microglial activation. Current acute ischemic stroke treatments, while effective in the general population, do not adequately address CKD-specific mechanisms, limiting their efficacy in this high-risk population. Prolyl hydroxylase domain (PHD) inhibitors have shown promise in treating anemia associated with CKD and may offer cerebroprotective benefits. However, the effects of PHD2 inhibition on long-term sensorimotor outcomes and the underlying mechanisms in mice with CKD remain largely unknown. Here, we investigated the impact of CKD on stroke severity and assessed the therapeutic potential of desidustat, a PHD inhibitor, in improving stroke outcomes. Using an adenine-induced CKD mouse model, we demonstrated that CKD exacerbated stroke-induced long-term sensorimotor deficits, increased neuroinflammation, and impaired microglial efferocytosis via dysregulation of the ADAM17-MerTK axis. Desidustat treatment in mice with CKD significantly improved long-term sensorimotor functional outcomes and reduced post-stroke neuroinflammation while enhancing microglial efferocytosis by reducing ADAM17 and enhancing microglial MerTK expression. In vitro studies using human-induced microglia-like cells further confirmed the ability of desidustat to enhance efferocytosis of apoptotic neurons by reducing the cleavage of MerTK. These findings suggest that desidustat may serve as a novel therapeutic strategy for improving stroke outcomes in patients with CKD, a population at high risk for stroke and poor functional recovery.
慢性肾脏病（CKD）患者发生中风的风险显著增加，中风预后较差，死亡率较高。CKD通过全身炎症、氧化应激和尿毒症毒素清除受损之间的复杂相互作用，加剧了中风风险和严重程度，导致神经炎症和小胶质细胞激活。目前的急性缺血性中风治疗方法虽然在普通人群中有效，但并未充分解决CKD特异性机制，限制了它们在这一高危人群中的疗效。脯氨酰羟化酶结构域（PHD）抑制剂在治疗与CKD相关的贫血方面已显示出前景，可能具有脑保护作用。然而，抑制PHD2对CKD小鼠长期感觉运动结果的影响及其潜在机制在很大程度上仍不清楚。在这里，我们研究了CKD对中风严重程度的影响，并评估了PHD抑制剂地西司他改善中风预后的治疗潜力。使用腺嘌呤诱导的CKD小鼠模型，我们证明CKD通过ADAM17-MerTK轴的失调加剧了中风诱导的长期感觉运动缺陷，增加了神经炎症，并损害了小胶质细胞的噬菌作用。对CKD小鼠进行地西司他治疗可显著改善长期感觉运动功能结果，减少中风后神经炎症，同时通过降低ADAM17和增强小胶质细胞MerTK表达来增强小胶质细胞的噬菌作用。使用人诱导的小胶质细胞样细胞进行的体外研究进一步证实了地西司他通过减少MerTK的裂解来增强凋亡神经元噬菌作用的能力。这些发现表明，地西司他可能是一种改善CKD患者中风预后的新治疗策略，CKD患者是中风和功能恢复不良的高危人群。
