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Map Kinases p38 And JNK Constitute Retrograde Stress Signals In Diabetic Neuropathy?
Author(s) -
Fernyhough P,
JD Delcroix,
Jude Eb,
Boulton Ajm,
Tomlinson Dr
Publication year - 2000
Publication title -
journal of the peripheral nervous system
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 67
eISSN - 1529-8027
pISSN - 1085-9489
DOI - 10.1046/j.1529-8027.2000.005003182.x
Subject(s) - p38 mitogen activated protein kinases , kinase , phosphorylation , diabetic neuropathy , medicine , endocrinology , blot , protein kinase a , mapk/erk pathway , diabetes mellitus , chemistry , biology , microbiology and biotechnology , biochemistry , gene
Stress‐activated protein kinases (SAPKs—p38 MAPK and JNK) are activated by high glucose or experimental diabetes. They are also carried from the periphery to the soma by retrograde axonal transport in sensory neurones. This study examined SAPK activation in nerve from diabetic patients and retrograde transport of activated SAPKs in diabetic rats. Sural nerve specimens were obtained from diabetic and roughly matched non‐diabetic individuals at amputation. Proteins were extracted for western blotting and blots exposed to antibodies raised against activated (phosphorylated on Ser/Thr) or all forms of JNK or p38, plus their common substrate, the transcription factor, ATF2. Retrograde transported SAPKs were collected distal to a 6h sciatic nerve crush in control and 8 wk streptozotocin diabetic rats. These were exposed to antibodies as described for human tissues. In human tissues, phosphorylation of JNK, p38 and ATF2 was increased between 2‐ to 4‐fold compared to controls. In rats, retrograde transport of phospho‐p38 (arbitrary units ± SD) was massively increased in diabetic rats (60.8 ± 11.8 versus controls, 18.8 ± 1.9) as was transport of ATF2 (20.9 ± 3.8 versus controls, 6.7 ± 0.8). One of the isoforms of phospho—JNK‐p46—showed a modest increase in retrograde transport in diabetic rats (13.7 ± 0.9 versus 8.1 ± 0.4), though the other isoforms (p54 and p56) were unaffected. These observations indicate a powerful retrograde signal in sensory neurones of diabetic rats in the form of exaggerated phosphorylation, and hence activation, of the SAPKs and one of their substrates, the transcription factor ATF2. This signal comes from some influence on the peripheral projection of these neurones and is a viable candidate for an early transcription‐dependent change in neuronal phenotype—perhaps a forerunner of diabetic neuropathy.