Rosiglitazone treatment reduces diabetic neuropathy in streptozotocin-treated DBA/2J mice

Abstract

Diabetic neuropathy (DN) is a common complication of diabetes. Currently, there is no drug treatment to prevent or slow the development of DN. Rosiglitazone (Rosi) is a potent insulin sensitizer and may also slow the development of DN by a mechanism independent of its effect on hyperglycemia. A two by two design was used to test the effect of Rosi treatment on the development of DN. Streptozotocin-induced diabetic DBA/2J mice were treated with Rosi. DN and oxidative stress were quantified, and gene expression was profiled using the Affymetrix Mouse Genome 430 2.0 microarray platform. An informatics approach identified key regulatory elements activated by Rosi. Diabetic DBA/2J mice developed severe hyperglycemia, DN, and elevated oxidative stress. Rosi treatment did not affect hyperglycemia but did reduce oxidative stress and prevented the development of thermal hypoalgesia. Two novel transcription factor binding modules were identified that may control genes correlated to changes in DN after Rosi treatment: SP1F_ZBPF and EGRF_EGRF. These targets may be useful in designing drugs with the same efficacy as Rosi in treating DN but with fewer undesirable effects.

Figure 1

DN and oxidative (Ox) stress measures. Panel A, Hind paw withdrawal latency was increased in diabetic (D) mice and reduced by Rosi treatment (D+Rosi). Panel, B, Sural sensory NCV was reduced in diabetic mice. Panel, C, Sciatic motor NCV was reduced in diabetic mice. Hind paw latency, sural sensory NCV, and sciatic motor NCV were not affected by Rosi treatment in control (C) mice (C, C plus Rosi). Panel D, The dityrosine to tyrosine ratio was increased in diabetic mice, and reduced by Rosi treatment. Dityrosine was still increased in diabetic mice treated with Rosi compared with control mice treated with Rosi. E, HODE was increased in diabetic mice and decreased by Rosi treatment. There was no difference between control and diabetic mice treated with Rosi. F, There is a significant correlation between thermal latency and dityrosine ratio. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Figure 2

Patterns of gene regulation. Each line is the fold change vs. control of one gene across the three different conditions. Genes regulated by both diabetes and Rosi were found to either increase with diabetes and decrease with Rosi treatment (A), or decrease in expression in diabetes and increase with Rosi treatment (B). C, The gene expression pattern of eight genes down-regulated by diabetes and up-regulated by Rosi was confirmed by real-time RT-PCR.

Figure 3

Significant promoter modules. The conserved binding motifs found to be significant by FrameWorker and GSEA. A, The SP1F_ZBPF motif. B, The EGRF_EGRF motif.