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Targeting apoptosis signalling kinase-1 (ASK-1) does not prevent the development of neuropathy in streptozotocin-induced diabetic mice.

Newton VL, Ali S, Duddy G, Whitmarsh AJ, Gardiner NJ - PLoS ONE (2014)

Bottom Line: Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38.As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy.Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.

ABSTRACT
Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n) mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy.

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ASK2 mRNA levels increase in the spinal cord of 4-week diabetic mice compared with controls.(A) ASK2 mRNA levels do not change in the DRG in diabetes, however there is a significant increase in ASK2 in spinal cords from 4-week diabetic mice compared with controls (B, *p<0.05; Student’s unpaired t-test). (C,D) Thioredoxin mRNA levels in DRG and lumbar spinal cord did not change significantly in diabetes. All values were normalised to cyclophilin B. Data are expressed as mean + SD; n = 5–6.
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pone-0107437-g003: ASK2 mRNA levels increase in the spinal cord of 4-week diabetic mice compared with controls.(A) ASK2 mRNA levels do not change in the DRG in diabetes, however there is a significant increase in ASK2 in spinal cords from 4-week diabetic mice compared with controls (B, *p<0.05; Student’s unpaired t-test). (C,D) Thioredoxin mRNA levels in DRG and lumbar spinal cord did not change significantly in diabetes. All values were normalised to cyclophilin B. Data are expressed as mean + SD; n = 5–6.

Mentions: Since ASK2 and thioredoxin are important regulatory proteins of ASK1, we investigated their expression levels in the DRG (Fig. 3A,C) and spinal cord (Fig. 3B,D) of diabetic and age-matched control mice. Whilst there was no significant change in ASK2 mRNA in the DRG (Fig. 3A), there was a significant increase in ASK2 in spinal cord samples after 4 weeks of diabetes, (Fig. 3B, p<0.05). In contrast, thioredoxin mRNA levels did not change in either tissue at these timepoints of diabetes (Fig. 3C,D).


Targeting apoptosis signalling kinase-1 (ASK-1) does not prevent the development of neuropathy in streptozotocin-induced diabetic mice.

Newton VL, Ali S, Duddy G, Whitmarsh AJ, Gardiner NJ - PLoS ONE (2014)

ASK2 mRNA levels increase in the spinal cord of 4-week diabetic mice compared with controls.(A) ASK2 mRNA levels do not change in the DRG in diabetes, however there is a significant increase in ASK2 in spinal cords from 4-week diabetic mice compared with controls (B, *p<0.05; Student’s unpaired t-test). (C,D) Thioredoxin mRNA levels in DRG and lumbar spinal cord did not change significantly in diabetes. All values were normalised to cyclophilin B. Data are expressed as mean + SD; n = 5–6.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4199525&req=5

pone-0107437-g003: ASK2 mRNA levels increase in the spinal cord of 4-week diabetic mice compared with controls.(A) ASK2 mRNA levels do not change in the DRG in diabetes, however there is a significant increase in ASK2 in spinal cords from 4-week diabetic mice compared with controls (B, *p<0.05; Student’s unpaired t-test). (C,D) Thioredoxin mRNA levels in DRG and lumbar spinal cord did not change significantly in diabetes. All values were normalised to cyclophilin B. Data are expressed as mean + SD; n = 5–6.
Mentions: Since ASK2 and thioredoxin are important regulatory proteins of ASK1, we investigated their expression levels in the DRG (Fig. 3A,C) and spinal cord (Fig. 3B,D) of diabetic and age-matched control mice. Whilst there was no significant change in ASK2 mRNA in the DRG (Fig. 3A), there was a significant increase in ASK2 in spinal cord samples after 4 weeks of diabetes, (Fig. 3B, p<0.05). In contrast, thioredoxin mRNA levels did not change in either tissue at these timepoints of diabetes (Fig. 3C,D).

Bottom Line: Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38.As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy.Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.

ABSTRACT
Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n) mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy.

Show MeSH
Related in: MedlinePlus