Work

Renal stress-associated extracellular vesicle signaling linked to lysosomal cathepsin D and NEK7–NLRP3 neuroinflammation

Year: 2026

Type: article

Abstract: Systemic exposure to neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) affects both the central nervous system (CNS) and peripheral organs; however, the contribution of peripheral organ stress to neuroinflammation remains incompletely understood. Here, we propose a peripheral-to-central signaling mechanism in which renal stress-associated extracellular vesicles (EVs) are linked to microglial inflammasome activation. Using computational and biochemical approaches, cathepsin D (CTSD) was identified as a molecular target of the MPTP metabolite 1-methyl-4-phenylpyridinium (MPP +). MPP + accumulated in renal tissue and was associated with lysosomal stress and tubular injury, accompanied by increased release of circulating EVs enriched with renal injury markers. Pharmacological inhibition of pepstatin A-sensitive lysosomal protease activity attenuated renal injury and EV release. MPTP exposure was also associated with blood-brain barrier disruption, potentially permitting circulating EV-associated signaling to influence the CNS. Plasma-derived EVs isolated under MPTP-treated conditions were associated with increased microglial activation, whereas pharmacological inhibition of EV biogenesis attenuated this response. Mechanistically, EV exposure was associated with inflammatory responses involving NIMA-related kinase 7 (NEK7)-NOD-like receptor family pyrin domain-containing 3-associated inflammatory signaling and IL-1β maturation. Consistent with these findings, NEK7 deficiency attenuated microglial activation and dopaminergic neuron loss in vivo. Together, these findings suggest that renal stress-associated EVs may be involved in linking peripheral stress to central neuroinflammatory responses. This study provides a tentative but verifiable framework for renal stress-EV-inflammasome communication in toxin-induced neuroinflammation.

Source: Molecular Biomedicine

DOI: 10.1186/s43556-026-00608-z

Authors: Gunhyuk Park, Ho-Ryong Yoo, Hye-Sun Lim

Institutions: Korea Institute of Oriental Medicine, Daejeon University

Language: English

Topic: Extracellular vesicles in disease

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,590