Calcimimetic restores diabetic peripheral neuropathy by ameliorating apoptosis and improving autophagy

Decreased AMPK-eNOS bioavailability mediates the development of diabetic peripheral neuropathy (DPN) through increased apoptosis and decreased autophagy activity in relation to oxidative stress. Schwann cells are responsible for maintaining structural and functional integrity of neurons and for repa...

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Bibliographic Details
Published in:Cell death & disease 2018-11, Vol.9 (12), p.1163-18, Article 1163
Main Authors: Chung, You Chul, Lim, Ji Hee, Oh, Hyun Mi, Kim, Hyung Wook, Kim, Min Young, Kim, Eun Nim, Kim, Yaeni, Chang, Yoon Sik, Kim, Hye Won, Park, Cheol Whee
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - drug effects
Autophagy
Autophagy - drug effects
Bcl-2 protein
Bioavailability
Calcium (intracellular)
Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics
Calcium-sensing receptors
Cinacalcet - pharmacology
Diabetes
Diabetes mellitus
Diabetic Neuropathies - drug therapy
Diabetic Neuropathies - genetics
Diabetic Neuropathies - pathology
Fibrosis
Gene Expression Regulation - drug effects
Humans
Intracellular signalling
LKB1 protein
Mice
Mice, Inbred NOD
Myelin
Nerve Degeneration - drug therapy
Nerve Degeneration - genetics
Nerve Degeneration - pathology
Nerves
Neurodegeneration
Nitric Oxide Synthase Type III - genetics
Oxidative stress
Oxidative Stress - drug effects
Peripheral Nervous System Diseases - drug therapy
Peripheral Nervous System Diseases - genetics
Peripheral Nervous System Diseases - pathology
Peripheral neuropathy
Phagocytosis
Phosphorylation
Protein Kinases - genetics
Protein-Serine-Threonine Kinases - genetics
Schwann cells
Schwann Cells - drug effects
Schwann Cells - pathology
Sciatic nerve
Sciatic Nerve - drug effects
Sciatic Nerve - pathology
Sensorimotor system
Signal transduction
Signal Transduction - drug effects
Structure-function relationships
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Summary:Decreased AMPK-eNOS bioavailability mediates the development of diabetic peripheral neuropathy (DPN) through increased apoptosis and decreased autophagy activity in relation to oxidative stress. Schwann cells are responsible for maintaining structural and functional integrity of neurons and for repairing damaged nerves. We evaluated the neuro-protective effect of cinacalcet on DPN by activating the AMPK-eNOS pathway using db/db mice and human Schwann cells (HSCs). Sciatic nerve of db/db mice was characterized by disorganized myelin, axonal shrinkage, and degeneration that were accompanied by marked fibrosis, inflammation, and apoptosis. These phenotypical alterations were significantly improved by cinacalcet treatment along with improvement in sensorimotor functional parameters. Cinacalcet demonstrated favorable effects through increased expression and activation of calcium-sensing receptor (CaSR)-CaMKKβ and phosphorylation of AMPK-eNOS signaling in diabetic sciatic nerve. Cinacalcet decreased apoptosis and increased autophagy activity in relation to decreased oxidative stress in HSCs cultured in high-glucose medium as well. This was accompanied by increased expression of the CaSR, intracellular Ca ([Ca ]i) levels, and CaMKKβ-LKB1-AMPK signaling pathway, resulting in the net effect of increased eNOS phosphorylation, NOx concentration, Bcl-2/Bax ratio, beclin 1, and LC3-II/LC3-I ratio. These results demonstrated that cinacalcet treatment ameliorates inflammation, apoptosis, and autophagy through increased expression of the CaSR, [Ca ]i levels and subsequent activation of CaMKKβ-LKB-1-AMPK-eNOS pathway in the sciatic nerve and HSCs under diabetic condition. Therefore, cinacalcet may play an important role in the restoration and amelioration of DPN by ameliorating apoptosis and improving autophagy.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-018-1192-7