title: 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 (AT(2)R) results in nerve facilitation. In this study, we determined the capacity of candesartan to correct expression patterns characteristic of neuropathy and AT(2)R-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(2)R 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(2)R and phosphorylated Akt expression. Furthermore, downregulation of phosphoinositide 3-kinase (PI3K) inhibited AT(2)R-mediated neurite outgrowth in control DRG cells. PI3K activation increased AT(2)R-mediated neurite outgrowth and phosphorylated Akt expression in FDR DRG cells. These results suggest that the decrease of AT(2)R-mediated neurite outgrowth in FDRs is likely to be the result of decreased PI3K-dependent Akt activation. Candesartan improved AT(2)R neuronal function and Akt phosphorylation, which were associated with sensory nerve defects and insulin sensitivity in the FDR.
authors.affiliation: Department of Life Science, Okayama University of Science, Kita-ku, Okayama, Japan. hobara@dls.ous.ac.jp
authors.forename: Narumi
authors.initials: N
authors.lastname: Hashikawa-Hobara
authors.forename: Naoya
authors.initials: N
authors.lastname: Hashikawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Inoue
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sanda
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Zamami
authors.forename: Shingo
authors.initials: S
authors.lastname: Takatori
authors.forename: Hiromu
authors.initials: H
authors.lastname: Kawasaki
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001786:Blood Glucose / Q000502:physiology; D005632:Fructose / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000502:physiology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D059225:Nociception / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D001786:Blood Glucose; D007328:Insulin; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D005632:Fructose; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C077793:candesartan cilexetil