Candesartan Cilexetil Improves Angiotensin II Type 2 Receptor–Mediated Neurite Outgrowth via the PI3K-Akt Pathway in Fructose-Induced Insulin-Resistant Rats

Abstract

We have shown previously that stimulation of the angiotensin II type 2 receptor (AT2R) results in nerve facilitation. In this study, we determined the capacity of candesartan to correct expression patterns characteristic of neuropathy and AT2R-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 AT2R 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 AT2R and phosphorylated Akt expression. Furthermore, downregulation of phosphoinositide 3-kinase (PI3K) inhibited AT2R-mediated neurite outgrowth in control DRG cells. PI3K activation increased AT2R-mediated neurite outgrowth and phosphorylated Akt expression in FDR DRG cells. These results suggest that the decrease of AT2R-mediated neurite outgrowth in FDRs is likely to be the result of decreased PI3K-dependent Akt activation. Candesartan improved AT2R neuronal function and Akt phosphorylation, which were associated with sensory nerve defects and insulin sensitivity in the FDR.

The Mechanism of Calcitonin Gene-Related Peptide^|^ndash;Containing Nerve Innervation

“…We found that the FDR developed insulin resistance and the density of CGRP-LI nerve fibers in the group of FDR was markedly decreased by approximately 20%, compared with age-matched control rats (27). In contrast, administration of the AT 1 -receptor antagonist candesartan cilexetil increased the density of CGRP-LI nerve fibers to control levels (27). In addition, FDR developed the downregulation of both AT 2 -receptor neuronal function and phosphorylated Akt expression in DRG neurons (27).…”

“…We examined whether the depression of CGRP nerves in FDR is related to AT 2 -receptor inactivation and whether treatment with the AT 1 -receptor antagonist candesartan cilexetil improves this depressed response. We found that the FDR developed insulin resistance and the density of CGRP-LI nerve fibers in the group of FDR was markedly decreased by approximately 20%, compared with age-matched control rats (27). In contrast, administration of the AT 1 -receptor antagonist candesartan cilexetil increased the density of CGRP-LI nerve fibers to control levels (27).…”

“…In contrast, administration of the AT 1 -receptor antagonist candesartan cilexetil increased the density of CGRP-LI nerve fibers to control levels (27). In addition, FDR developed the downregulation of both AT 2 -receptor neuronal function and phosphorylated Akt expression in DRG neurons (27). Candesartan improved neurite outgrowth in FDR, which was associated with the restoration of AT 2 receptor and phosphorylated Akt expression (27).…”

“…Akt is activated by insulin or various growth factors to function in a phosphoinositide 3-kinase (PI3K)-sensitive pathway. Furthermore, downregulation of PI3K inhibited AT 2 receptor-mediated neurite outgrowth in control DRG cells, indicating that insulin resistance induces the downregulation of AT 2 -receptor function (27) because PI3K inhibition results in insulin resistance (28). In contrast, PI3K activation increased AT 2 receptor-mediated neurite outgrowth and phosphorylated Akt expression in FDR DRG cells (27).…”

“…In addition, FDR developed the downregulation of both AT 2 -receptor neuronal function and phosphorylated Akt expression in DRG neurons (27). Candesartan improved neurite outgrowth in FDR, which was associated with the restoration of AT 2 receptor and phosphorylated Akt expression (27). Akt is activated by insulin or various growth factors to function in a phosphoinositide 3-kinase (PI3K)-sensitive pathway.…”