title: Two types of overcontraction are involved in intrarenal artery dysfunction in type II diabetic mouse.
abstract: Contractile responses in small intrarenal arteries are associated with diabetic nephropathy. However, the mechanisms that induce and maintain altered small vessel contraction are not clearly understood. To further understand intrarenal artery dysfunction in diabetes, phenylephrine (PE)-induced force development was assessed in the intrarenal artery [interlobar artery (ILA)] in control (lean) and type II diabetic (ob/ob) mice. PE-induced dose-dependent force development in the ILA was significantly greater in ob/ob mice than in lean mice (592.8 ± 5.2 and 770.1 ± 12.1 µ/mm tissue, respectively, following administration of 30 µM PE, n = 5). Under high-glucose conditions (twice the normal concentration of glucose), PE-induced force development in the ILA was only enhanced in ob/ob mice (946.0 ± 18.2 µN/mm tissue; n = 5). ILA dysfunction reduces blood flow to the glomerulus and may induce diabetic nephropathy. Basal overcontraction of the ILA in ob/ob mice under normal-glucose conditions was reduced by pretreatment with rottlerin, a calcium-independent protein kinase C (PKCδ) inhibitor. Total PKC activity was also reduced by rottlerin. Under high-glucose conditions, the enhanced ILA contraction in diabetic mice was suppressed by rho A and rho kinase inhibitors. Our results indicate two types of ILA dysfunction in diabetes, as follows: 1) a basal increase in PE-induced contraction under normal-glucose conditions, and 2) extracellular glucose-dependent enhancement of PE-induced contraction. We believe that these dysfunctions are mediated by the activation of the PKCδ and rho A-rho kinase pathways, respectively.
authors.affiliation: Laboratory of Physiology, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan (K.N., Y.T., K.K.); and Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan (T.H., K.H.) kojinobe@josai.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Nobe
authors.affiliation: Laboratory of Physiology, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan (K.N., Y.T., K.K.); and Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan (T.H., K.H.).
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takenouchi
authors.affiliation: Laboratory of Physiology, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan (K.N., Y.T., K.K.); and Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan (T.H., K.H.).
authors.forename: Keizo
authors.initials: K
authors.lastname: Kasono
authors.affiliation: Laboratory of Physiology, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan (K.N., Y.T., K.K.); and Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan (T.H., K.H.).
authors.forename: Terumasa
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Physiology, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan (K.N., Y.T., K.K.); and Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan (T.H., K.H.).
authors.forename: Kazuo
authors.initials: K
authors.lastname: Honda
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012077:Renal Artery / Q000187:drug effects / Q000503:physiopathology*; D012079:Renal Circulation; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D001786:Blood Glucose; D047428:Protein Kinase Inhibitors; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; C085746:rottlerin; D011493:Protein Kinase C