Kallikrein-Kinin System Applications in Ischemic Stroke Management

The kallikrein–kinin system constitutes a proteolytic cascade that generates kinins, notably bradykinin, which regulate vascular tone, permeability and inflammatory responses. In the context of ischaemic stroke, modulation of this system has emerged as a dual-phase therapeutic approach: during the acute ischaemic phase, kallikrein supplementation enhances protective signalling pathways to preserve the integrity of the neurovascular unit, while in the reperfusion phase, kinin-mediated effects can be harnessed to attenuate oxidative stress, inflammation and endothelial barrier dysfunction. Preclinical models have demonstrated that tissue kallikrein or kallidinogenase administration activates bradykinin B2 receptors to engage PI3K–AKT–HIF-1α signalling, up-regulate VEGF and eNOS, and reduce neuronal apoptosis. Clinically, human urinary kallidinogenase infusions have shown favourable safety profiles and significant improvements in neurological function and long-term independence, marking a promising translational pathway for kinin-based adjunct therapies in stroke management.

Research from Nature Portfolio

Recent studies have investigated vespakinin-M, a naturally occurring bradykinin-like peptide derived from wasp venom. In murine models of middle cerebral artery occlusion, systemic administration of vespakinin-M promoted functional recovery by reducing infarct volume, preserving blood–brain barrier integrity and suppressing neuroinflammation and oxidative damage. Mechanistically, vespakinin-M was shown to bind bradykinin B2 receptors, triggering PI3K–AKT activation and inhibiting IκBα–NF-κB signalling, thereby limiting apoptotic and inflammatory cascades and highlighting a novel peptide-based therapeutic strategy targeting the kallikrein–kinin axis.

Kallikrein-Kinin System Applications in Ischemic Stroke Management publication trend

The graph below shows the total number of articles in kallikrein-kinin system applications in ischemic stroke management across all publications each year (not limited to Nature Index journals).

Technical terms

Kallikrein–Kinin System (KKS): A proteolytic pathway that converts kininogens into active kinins, regulating vascular and inflammatory processes.

Bradykinin: A vasoactive peptide generated by kallikrein cleavage of kininogen, modulating vasodilation, permeability and inflammation.

Neurovascular Unit (NVU): The functional ensemble of neurons, glia, endothelial cells and pericytes that maintain cerebral blood flow and blood–brain barrier integrity.

Bradykinin B2 Receptor (B2R): A constitutively expressed G protein–coupled receptor for bradykinin that mediates cytoprotective and vasodilatory responses.

PI3K–AKT Signalling: An intracellular kinase cascade promoting cell survival, metabolism and angiogenesis, activated by receptor-mediated stimuli.

HIF-1α: Hypoxia-inducible factor 1-alpha, a transcription factor stabilised under low oxygen that drives expression of genes involved in angiogenesis and metabolic adaptation.

VEGF: Vascular endothelial growth factor, a key mediator of angiogenesis and vascular permeability.

eNOS: Endothelial nitric oxide synthase, an enzyme that produces nitric oxide to regulate vascular tone and endothelial function.

References

1. Tissue Kallikrein supplementation in ischemic phase protects the neurovascular unit and attenuates reperfusion-induced injury in ischemic stroke. Pharmacological Research (2024).
2. Vespakinin-M, a natural peptide from Vespa magnifica, promotes functional recovery in stroke mice. Communications Biology (2022).
3. Human urinary kallidinogenase in acute ischemic stroke: A single‐arm, multicenter, phase IV study (RESK study). CNS Neuroscience & Therapeutics (2021).