Candesartan cilexetil improves angiotensin II type 2 receptor-mediated neurite outgrowth via the PI3K-Akt pathway in fructose-induced insulin-resistant rats

We have shown previously that stimulation of the angiotensin II type 2 receptor (AT ₂R) results in nerve facilitation. In this study, we determined the capacity of candesartan to correct expression patterns characteristic of neuropathy and AT ₂R-mediated neurite outgrowth in the fructose-induced insulin-resistant rat, which is one of the human hyperinsulinemia models. Wistar rats received a 15% (w/v) fructose solution in their drinking water for 4 weeks (fructose-drinking rats [FDRs]), with or without candesartan (5 mg/kg/day). We evaluated physiological and behavioral parameters and performed immunohistochemical studies. We found that the FDR developed insulin resistance and downregulated both AT ₂R neuronal function and phosphorylated Akt expression in dorsal root ganglia (DRG) neurons. Candesartan improved neurite outgrowth in the FDR, which was associated with the restoration of AT ₂R and phosphorylated Akt expression. Furthermore, downregulation of phosphoinositide 3-kinase (PI3K) inhibited AT ₂R-mediated neurite outgrowth in control DRG cells. PI3K activation increased AT ₂R-mediated neurite outgrowth and phosphorylated Akt expression in FDR DRG cells. These results suggest that the decrease of AT ₂R-mediated neurite outgrowth in FDRs is likely to be the result of decreased PI3K-dependent Akt activation. Candesartan improved AT ₂R neuronal function and Akt phosphorylation, which were associated with sensory nerve defects and insulin sensitivity in the FDR.