Early gene responses of trophic factors in nerve regeneration differ in experimental type 1 and type 2 diabetic polyneuropathies.
We have previously suggested that alterations in sequential early gene responses of trophic factors (IGF-1 -->c-fos-->NGF) contribute to impaired peripheral nerve regeneration in type 1 diabetic BB/W-rats. To study the role these responses may play in type 2 diabetic nerve regeneration, BB/Z-rats were subjected to sciatic nerve crush injury. The expression of IGF-1, c-fos, NGF and the receptors p75 and IGF-1R were determined at the protein and mRNA levels in sciatic nerve distal to the crush site by immunoblotting and semi-quantitative RT-PCR. In situ hybridization was performed to assess the cellular localization of IGF-1, NGF, p75, and IGF-1R mRNA and immunohistochemistry served to localize the source of p75 and IGF-1R protein expression. The data were compared to those of type 1 diabetic BB/Wor-rats and non-diabetic controls. Increased expression of IGF-1 in Schwann cells is the first growth factor response to injury and peaked at 0.5 hours (h) in control, 2 h in type 2 rats, and 24 h in type 1 rats. IGF-1R was expressed in Schwann cells and its expression was asynchronous to IGF-1 expression in type 1 rats but remained synchronous with IGF-1 in control and type 2 animals. The expression of the immediate early proto-oncogene c-fos exhibited an initial peak at 6 h in control animals, 24 h in type 2, and 2 days (d) in type 1 animals. The initial peak of NGF expression occurred at 6 h in non-diabetic rats, 24 h in type 2, and 2 d in type 1 diabetic rats. The expression of p75 was delayed and attenuated in type 1 diabetic rats; however, in type 2 diabetic rats it was similar to that of non-diabetic rats. These data indicate that early gene responses following nerve damage are significantly less perturbed in type 2 compared to type 1 diabetes. These differences may account for the more efficient nerve regeneration seen in type 2 diabetic polyneuropathy.
Pierson
Christopher R
CR
Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Zhang
Weixian
W
Murakawa
Yuichi
Y
Sima
Anders A F
AA
D000818:Animals; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003929:Diabetic Neuropathies / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000235:genetics*; D016133:Polymerase Chain Reaction; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D011913:Rats, Inbred BB; D020800:Receptor, Nerve Growth Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology
D017931:DNA Primers; D016760:Proto-Oncogene Proteins c-fos; D020800:Receptor, Nerve Growth Factor; D007334:Insulin-Like Growth Factor I