Discordant effects of guanidines on renal structure and function and on regional vascular dysfunction and collagen changes in diabetic rats.
We examined the effects of aminoguanidine and methylguanidine on vascular dysfunction, glomerular structural changes, and indexes of early and late nonenzymatic glycation in 7-month streptozotocin-induced diabetic rats. Kidney weight, glomerular volume, fractional mesangial volume, glomerular capillary basement membrane width, and urinary albumin excretion were increased in diabetic rats. Diabetes also 1) increased vascular albumin permeation twofold in retina, sciatic nerve, aorta, skin, and kidney; 2) decreased renal collagenase-soluble collagen; 3) increased collagen-associated fluorescence in kidney and skin but not in aorta; and 4) increased glycated hemoglobin levels and aortic pentosidine levels. Aminoguanidine reduced albuminuria by 70% after 4 months, and both guanidines 1) normalized aortic pentosidine levels and renal collagenase-soluble collagen, 2) had no effect on glycated hemoglobin levels or collagen-associated fluorescence (in aorta, kidney, or skin), and 3) had little or no effect on regional albumin permeation. These discordant effects of aminoguanidine on diabetes-induced vascular changes versus parameters of nonenzymatic glycation are consistent with a multifactorial pathogenesis of diabetic complications, including roles for metabolic imbalances independent of nonenzymatic glycation. To the extent that glomerular matrix accumulation and increased regional albumin permeation in chronically diabetic rats are sequelae of nonenzymatic glycation, these findings point to an important role for early glycation reactions and products.
Nyengaard
J R
JR
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Chang
K
K
Berhorst
S
S
Reiser
K M
KM
Williamson
J R
JR
Tilton
R G
RG
D000419:Albuminuria; D000818:Animals; D001485:Basement Membrane / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002196:Capillaries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002302:Cardiac Output / Q000187:drug effects; D003094:Collagen / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005247:Feeding Behavior / Q000187:drug effects; D005920:Glomerular Mesangium / Q000473:pathology / Q000503:physiopathology; D006442:Glycated Hemoglobin / Q000032:analysis; D006031:Glycosylation; D006146:Guanidines / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008760:Methylguanidine / Q000494:pharmacology*; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects*; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D012584:Sciatic Nerve / Q000098:blood supply; D012867:Skin / Q000098:blood supply; D014655:Vascular Resistance / Q000187:drug effects
D001786:Blood Glucose; D003094:Collagen; D006442:Glycated Hemoglobin; D006146:Guanidines; D008760:Methylguanidine; C004479:pimagedine