Caveolin-1 and altered neuregulin signaling contribute to the pathophysiological progression of diabetic peripheral neuropathy.
OBJECTIVE
Evaluate if Erb B2 activation and the loss of caveolin-1 (Cav1) contribute to the pathophysiological progression of diabetic peripheral neuropathy (DPN).


METHODS
Cav1 knockout and wild-type C57BL/6 mice were rendered diabetic with streptozotocin, and changes in motor nerve conduction velocity (MNCV), mechanical and thermal hypoalgesia, Erb B2 phosphorylation (pErb B2), and epidermal nerve fiber density were assessed. The contribution of Erb B2 to DPN was assessed using the Erb B2 inhibitors PKI 166 and erlotinib and a conditional bitransgenic mouse that expressed a constitutively active form of Erb B2 in myelinated Schwann cells (SCs).


RESULTS
Diabetic mice exhibited decreased MNCV and mechanical and thermal sensitivity, but the extent of these deficits was more severe in diabetic Cav1 knockout mice. Diabetes increased pErb B2 levels in both genotypes, but the absence of Cav1 correlated with a greater increase in pErb B2. Erb B2 activation contributed to the mechanical hypoalgesia and MNCV deficits in both diabetic genotypes because treatment with erlotinib or PKI 166 improved these indexes of DPN. Similarly, induction of a constitutively active Erb B2 in myelinated SCs was sufficient to decrease MNCV and induce a mechanical hypoalgesia in the absence of diabetes.


CONCLUSIONS
Increased Erb B2 activity contributes to specific indexes of DPN, and Cav1 may be an endogenous regulator of Erb B2 signaling. Altered Erb B2 signaling is a novel mechanism that contributes to SC dysfunction in diabetes, and inhibiting Erb B2 may ameliorate deficits of tactile sensitivity in DPN.
McGuire
James F
JF
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas, USA.
Rouen
Shefali
S
Siegfreid
Eric
E
Wright
Douglas E
DE
Dobrowsky
Rick T
RT
D000698:Analgesia; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology; D009412:Nerve Fibers / Q000473:pathology / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009431:Neural Conduction / Q000502:physiology; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology*
D001786:Blood Glucose; D051242:Caveolin 1; D009419:Nerve Tissue Proteins
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