title: Glomerular-specific protein kinase C-β-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity.
abstract: Insulin resistance has been associated with the progression of chronic kidney disease in both diabetes and obesity. In order to determine the cellular mechanisms contributing to this, we characterized insulin signaling in renal tubules and glomeruli during diabetic and insulin-resistant states using streptozotocin-diabetic and Zucker fatty-insulin-resistant rats. Compared with nondiabetic and Zucker lean rats, the insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1), Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α were selectively inhibited in the glomeruli but not in the renal tubules of both respective models. Protein, but not mRNA levels of IRS1, was decreased only in the glomeruli of streptozotocin-diabetic rats likely due to increased ubiquitination. Treatment with the protein kinase C-β inhibitor, ruboxistaurin, enhanced insulin actions and elevated IRS1 expression. In glomerular endothelial cells, high glucose inhibited the phosphorylation of Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α; decreased IRS1 protein expression and increased its association with ubiquitin. Overexpression of IRS1 or the addition of ruboxistaurin reversed the inhibitory effects of high glucose. Thus, loss of insulin's effect on endothelial nitric oxide synthase and glycogen synthase kinase 3α activation may contribute to the glomerulopathy observed in diabetes and obesity.
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Ohshiro
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.forename: Motonobu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Pedro
authors.initials: P
authors.lastname: Geraldes
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Gregory S
authors.initials: GS
authors.lastname: White
authors.forename: Christopher
authors.initials: C
authors.lastname: Cahill
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation; D061988:Proteasome Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D007211:Indoles; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D008301:Maleimides; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D009569:Nitric Oxide; C099154:ruboxistaurin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha