Aminoguanidine and ramipril prevent diabetes-induced increases in protein kinase C activity in glomeruli, retina and mesenteric artery.
This study investigated the effects of insulin therapy, inhibition of advanced glycation end-product formation with aminoguanidine and angiotensin-converting enzyme inhibition with ramipril on diabetes-related increases in protein kinase C (PKC) activity in the streptozotocin-diabetic rat. PKC activity in the glomeruli, retina and mesenteric artery was increased by 1.5-2-fold after induction of diabetes, and this increase was maintained over 24 weeks. Treatment with insulin at 2 units or 6 units per day attenuated glomerular PKC in proportion to the level of glycohaemoglobin after 4 weeks of diabetes (r=0.68, P<0.0001). The higher dose of insulin prevented the diabetes-related increase in glomerular PKC activity, although blood glucose levels were not normalized. After 8 weeks of diabetes, ramipril completely prevented the diabetes-related increases in PKC activity in the glomeruli, retina and mesenteric artery. By contrast, aminoguanidine treatment resulted in no inhibition of glomerular PKC activity, partial inhibition of retinal PKC activity and complete inhibition of mesenteric artery PKC activity. After 24 weeks of diabetes, both aminoguanidine and ramipril prevented the diabetes-related increases in PKC activity in all three tissues, in parallel with suppression of albuminuria by both agents. Aminoguanidine also prevented diabetes-related increases in retinal permeability at 16 weeks. These results suggest that the organ-protective effects of insulin, aminoguanidine and ramipril in diabetes may be mediated, at least in part, through the differential inhibition of PKC activity in various tissues.
Osicka
T M
TM
Endocrine Unit, Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia.
Yu
Y
Y
Lee
V
V
Panagiotopoulos
S
S
Kemp
B E
BE
Jerums
G
G
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000032:analysis; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism; D006146:Guanidines / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D017257:Ramipril / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006442:Glycated Hemoglobin; D017127:Glycation End Products, Advanced; D006146:Guanidines; D007004:Hypoglycemic Agents; D007328:Insulin; D011493:Protein Kinase C; D017257:Ramipril; C004479:pimagedine