Signal transduction through Ras-GTPase and Ca2+/ calmodulin-dependent protein kinase II contributes to development of diabetes-induced renal vascular dysfunction.
This study examined the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Ras-GTPase in the development of abnormal reactivity to vasoactive agents in the renal artery of diabetic rats. The vasoconstrictor response induced by norepinephrine (NE), endothelin-1 (ET-1) or angiotensin II (Ang II) was significantly increased whereas vasodilator response to carbachol, histamine or sodium nitroprusside (SNP) was not altered in the renal artery segments of the streptozotocin (STZ)-diabetic rats. Chronic intraperitoneal administration of KN-93 (5 mg/kg/ alt diem), an inhibitor of CaMKII or FPTIII (1.5 mg/kg/ alt diem), an inhibitor of Ras-GTPase, produced significant normalization of the altered agonist-induced vasoconstrictor responses without affecting blood glucose levels. All the inhibitors were administered for four weeks starting from day one of diabetes induction. Inhibition of Ras-GTPase or CaMKII did not affect the agonist-induced vasoconstrictor and vasodilator responses in the non-diabetic control animals. These data suggest that inhibition of signal transduction involving CaMKII and Ras-GTPase can prevent development of diabetes-induced abnormal vascular reactivity in the renal artery.
Yousif
Mariam H M
MH
Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, P. O. Box: 24923, Safat 13110, Kuwait. mariam@hsc.edu.kw
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000503:physiopathology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000187:drug effects / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery / Q000187:drug effects / Q000503:physiopathology; D015398:Signal Transduction; D013311:Streptozocin; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D018631:ras Proteins / Q000187:drug effects / Q000378:metabolism*
C436083:2-(2-oxo-2-((3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy)aminoethyl)phosphonic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester sodium; D063065:Organophosphonates; D013311:Streptozocin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020558:GTP Phosphohydrolases; D018631:ras Proteins