Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy.
Animals
Behavior, Animal
Blood-Nerve Barrier
/ metabolism
Capillary Permeability
Claudin-1
/ genetics
Diabetic Neuropathies
/ chemically induced
Disease Models, Animal
Down-Regulation
Hyperalgesia
/ chemically induced
Macrophages
/ metabolism
Male
Motor Activity
Pain Threshold
Rats, Wistar
Streptozocin
Tight Junctions
/ genetics
Barrier
Macrophages
Neuropathy
Pain
Journal
Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Titre abrégé: J Mol Med (Berl)
Pays: Germany
ID NLM: 9504370
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
24
11
2020
accepted:
10
05
2021
revised:
26
04
2021
pubmed:
22
5
2021
medline:
9
2
2022
entrez:
21
5
2021
Statut:
ppublish
Résumé
Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage. KEY MESSAGES: • In diabetic painful neuropathy in rats: • Blood nerve barrier and blood DRG barrier are leaky for micromolecules. • Perineurial Cldn1 sealing the blood nerve barrier is specifically downregulated. • Endoneurial vessel-associated macrophages are also decreased. • These changes occur after onset of hyperalgesia thereby maintaining rather than inducing pain.
Identifiants
pubmed: 34018017
doi: 10.1007/s00109-021-02091-1
pii: 10.1007/s00109-021-02091-1
pmc: PMC8367905
doi:
Substances chimiques
Claudin-1
0
Cldn1 protein, rat
0
Streptozocin
5W494URQ81
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1237-1250Informations de copyright
© 2021. The Author(s).
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