Tissue kallikrein attenuates early ischemic edema by facilitating glymphatic system kinetics in pMCAO mice
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GRAPHICAL ABSTRACT
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PUBLIC SUMMARY
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Glymphatic kinetics maintain brain homeostasis via fluid influx-efflux and modulate cerebral edema.
Our previous study confirmed impaired glymphatic transport in permanent middle cerebral artery occlusion mice.
Tissue kallikrein induces cerebrovascular vasodilation and subsequently facilitates glymphatic fluid dynamics.
This study underscores the need for clinical studies to explore TK's impact on ischemic edema.
TK mitigated brain edema in pMCAO mice with prolonged DWI/T2 mismatch, probably by boosting glymphatic efflux.
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ABSTRACT
The glymphatic system (GS) maintains brain fluid homeostasis and is potentially associated with cerebral ischemic edema. Tissue kallikrein (TK) enhances local cerebrovascular vasodilation and facilitates the GS kinetics. Herein, this study hypothesized that TK could relieve early ischemic edema after vascular occlusion by altering glymphatic dynamics. In permanent middle cerebral artery occlusion (pMCAO) models, brain water content was measured to evaluate edema severity, diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) mismatch—defined as an acute ischemic lesion observed in DWI not corresponding to a lesion in T2WI—was employed to assess edema progression. The fluorescent tracer OVA-647 was injected into the mouse striatum to quantify interstitial fluid (ISF) perfusion in the brain parenchyma and fluid outflow to the deep cervical lymph nodes (dCLNs). Immunohistochemistry was further applied to assess aquaporin-4 (AQP4) expression on the ventricular ependymal walls. Statistical results showed that TK-treated mice exhibited a significantly extended DWI/T2WI mismatch duration (98.0 ± 11.43 min vs. 63.0 ± 8.08 min; P =0.0286 ) and lower ipsilateral brain water content at 24 hours (P =0.0159 ). Meanwhile, the cerebrospinal fluid (CSF)/ISF tracer area fraction in the striatum was increased, and dCLN fluorescence intensity rose markedly (P =0.0349 and P =0.0002 , respectively), alongside upregulated AQP4 expression in the ependymal wall (P =0.0016 ). To conclude, TK effectively alleviates ischemic brain edema in pMCAO mice, as validated by reduced tissue water content and a prolonged DWI/T2WI mismatch. Its protective function is realized by upregulating ependymal AQP4 to boost glymphatic fluid perfusion and clearance.-
Keywords:
- kallikrein /
- ischemic edema /
- MCAO /
- glymphatic /
- CSF /
- kinetics
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REFERENCES
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Zhang J., Shen W., Tao Y., et al. (2026). Tissue kallikrein attenuates early ischemic edema by facilitating glymphatic system kinetics in pMCAO mice. The Innovation Neurology 1:100011. https://doi.org/10.59717/j.xinn-tine.2026.100011
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Zhang J., Shen W., Tao Y., et al. (2026). Tissue kallikrein attenuates early ischemic edema by facilitating glymphatic system kinetics in pMCAO mice. The Innovation Neurology 1:100011. https://doi.org/10.59717/j.xinn-tine.2026.100011
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Figure 1.
Treatment with TK following pMCAO reduced cerebral infarction volume and alleviated tissue edema
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Figure 2.
Treatment with TK after pMCAO attenuated the progression of brain edema
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Figure 3.
Interstitial fluid perfusion and drainage were immediately impaired following pMCAO and reversed by TK treatment
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Figure 4.
Immunohistochemical staining of AQP4 in ependymal wall
