Journal article
Prolyl hydroxylase inhibitor desidustat improves stroke outcomes via enhancing efferocytosis in mice with chronic kidney disease
Experimental neurology, Vol.386, 115181
04/2025
DOI: 10.1016/j.expneurol.2025.115181
PMCID: PMC12063501
PMID: 39914641
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.
Details
- Title: Subtitle
- Prolyl hydroxylase inhibitor desidustat improves stroke outcomes via enhancing efferocytosis in mice with chronic kidney disease
- Creators
- Harpreet Kaur - Louisiana State University Health Sciences Center ShreveportNilesh Pandey - Louisiana State University Health Sciences Center ShreveportLakshmi Chandaluri - Louisiana State University Health Sciences Center ShreveportNirvana Shaaban - Louisiana State University Health Sciences Center ShreveportAlexa Martinez - Louisiana State University Health Sciences Center ShreveportEvan Kidder - Louisiana State University Health Sciences Center ShreveportVishal J Patel - Cadila HealthcareSamadhan G Kshirsagar - Cadila HealthcareDhananjay Kumar - Louisiana State University Health Sciences Center ShreveportLouise Frausto - Louisiana State University Health Sciences Center ShreveportRajan Pandit - Louisiana State University Health Sciences Center ShreveportKoral S E Richard - Louisiana State University Health Sciences Center ShreveportSumit Kumar Anand - Louisiana State University Health Sciences Center ShreveportSandeep Das - Louisiana State University Health Sciences Center ShreveportAjit Vikram - University of IowaTarek Magdy - Louisiana State University Health Sciences Center ShreveportXiao-Hong Lu - Louisiana State University Health Sciences Center ShreveportA Wayne Orr - Louisiana State University Health Sciences Center ShreveportHarilal Patel - Cadila HealthcareRavi Kumar Trivedi - Cadila HealthcareKevinkumar Kansagra - Cadila HealthcareAmit A Joharapurkar - Cadila HealthcareDeven V Parmar - Zydus PharmaceuticalsMukul R Jain - Cadila HealthcareOren Rom - Louisiana State University Health Sciences Center ShreveportArif Yurdagul Jr - Louisiana State University Health Sciences Center ShreveportNirav Dhanesha - Louisiana State University Health Sciences Center Shreveport
- Resource Type
- Journal article
- Publication Details
- Experimental neurology, Vol.386, 115181
- DOI
- 10.1016/j.expneurol.2025.115181
- PMID
- 39914641
- PMCID
- PMC12063501
- NLM abbreviation
- Exp Neurol
- ISSN
- 0014-4886
- eISSN
- 1090-2430
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE; SAN DIEGO
- Grant note
- R01 HL167773 / NHLBI NIH HHS
- Language
- English
- Electronic publication date
- 02/04/2025
- Date published
- 04/2025
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984786443502771
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