TY - JOUR
T1 - Candesartan cilexetil improves angiotensin II type 2 receptor-mediated neurite outgrowth via the PI3K-Akt pathway in fructose-induced insulin-resistant rats
AU - Hashikawa-Hobara, Narumi
AU - Hashikawa, Naoya
AU - Inoue, Yusuke
AU - Sanda, Hitomi
AU - Zamami, Yoshito
AU - Takatori, Shingo
AU - Kawasaki, Hiromu
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/4
Y1 - 2012/4
N2 - 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.
AB - 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.
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U2 - 10.2337/db11-1468
DO - 10.2337/db11-1468
M3 - Article
C2 - 22357959
AN - SCOPUS:84859529833
VL - 61
SP - 925
EP - 932
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 4
ER -