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. 2025 Apr:386:115181.
doi: 10.1016/j.expneurol.2025.115181. Epub 2025 Feb 4.

Prolyl hydroxylase inhibitor desidustat improves stroke outcomes via enhancing efferocytosis in mice with chronic kidney disease

Harpreet Kaur  1 , Nilesh Pandey  1 , Lakshmi Chandaluri  1 , Nirvana Shaaban  1 , Alexa Martinez  1 , Evan Kidder  1 , Vishal J Patel  2 , Samadhan G Kshirsagar  2 , Dhananjay Kumar  3 , Louise Frausto  3 , Rajan Pandit  3 , Koral S E Richard  1 , Sumit Kumar Anand  1 , Sandeep Das  1 , Ajit Vikram  4 , Tarek Magdy  1 , Xiao-Hong Lu  5 , A Wayne Orr  6 , Harilal Patel  7 , Ravi Kumar Trivedi  7 , Kevinkumar Kansagra  8 , Amit A Joharapurkar  2 , Deven V Parmar  9 , Mukul R Jain  2 , Oren Rom  6 , Arif Yurdagul Jr  3 , Nirav Dhanesha  10
Affiliations

Prolyl hydroxylase inhibitor desidustat improves stroke outcomes via enhancing efferocytosis in mice with chronic kidney disease

Harpreet Kaur et al. Exp Neurol. 2025 Apr.

Abstract

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.

Keywords: Chronic kidney disease; Efferocytosis; PHD inhibitors; Sensorimotor recovery; Stroke.

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Conflict of interest statement

Declaration of competing interest Vishal J. Patel, Samadhan G. Kshirsagar, Harilal Patel, Ravi Kumar Trivedi, Kevinkumar Kansagra, Amit A. Joharapurkar, Deven V. Parmar, and Mukul R. Jain are employees of Zydus Lifesciences. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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