title: Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression.
abstract: Renin is the rate-limiting enzyme in renin-angiotensin system (RAS) activation. We sought to determine the impact of renin inhibition on whole-body insulin sensitivity and skeletal muscle RAS, oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2), which manifests increased tissue RAS activity, elevated serum aldosterone, hypertension, and insulin resistance. Young (aged 6-9 wk) Ren2 and age-matched Sprague Dawley control rats were treated with aliskiren [50 mg/kg . d, ip] or placebo for 21 d and administered an ip glucose tolerance test. Insulin metabolic signaling and 2-deoxyglucose uptake in soleus muscle were examined in relation to tissue renin-angiotensin-aldosterone system [angiotensin (Ang) II, mineralocorticoid receptor (MR), and Ang type I receptor (AT(1)R)] and measures of oxidative stress as well as structural changes evaluated by light and transmission electron microscopy. Ren2 rats demonstrated systemic insulin resistance with decreased skeletal muscle insulin metabolic signaling and glucose uptake. This was associated with increased Ang II, MR, AT(1)R, oxidative stress, and reduced tyrosine insulin receptor substrate-1 phosphorylation, protein kinase B/(Akt) phosphorylation and glucose transporter-4 immunostaining. The Ren2 also demonstrated perivascular fibrosis and mitochondrial remodeling. Renin inhibition improved systemic insulin sensitivity, insulin metabolic signaling, and glucose transport along with normalization of Ang II, AT(1)R, and MR levels, oxidative stress markers, fibrosis, and mitochondrial structural abnormalities. Our data suggest that renin inhibition improves systemic insulin sensitivity, skeletal muscle insulin metabolic signaling, and glucose transport in Ren2 rats. This is associated with reductions in skeletal muscle tissue Ang II, AT(1)R, and MR expression; oxidative stress; fibrosis; and mitochondrial abnormalities.
authors.affiliation: Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Lastra
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Adam T
authors.initials: AT
authors.lastname: Whaley-Connell
authors.forename: Camila
authors.initials: C
authors.lastname: Manrique
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Jenna
authors.initials: J
authors.lastname: Rehmer
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Patel
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferrario
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D005650:Fumarates / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000804:Angiotensin II; D005650:Fumarates; D005947:Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D051057:Proto-Oncogene Proteins c-akt; D026361:Reactive Nitrogen Species; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D012083:Renin; D000092502:Renin Inhibitors; C526296:Irs1 protein, rat; C535029:Ren2 protein, rat; C495694:Slc2a4 protein, rat; C446481:aliskiren