Aldose reductase and the development of renal disease in diabetic dogs.
Effects of 5 years administration of an aldose reductase inhibitor (Sorbinil) on renal structure and albumin excretion were evaluated in diabetic dogs. Glycemia, estimated by frequent measurements of HbA1, glycated plasma proteins and glucosuria, was kept comparable between the placebo- and Sorbinil-treated diabetic groups. Kidney structure was evaluated using morphometric techniques by light and electron microscopy, and excretion of immunoreactive albumin was measured yearly. Placebo-treated diabetic dogs developed nephromegaly, glomerular enlargement, increased mesangial volume, and basement membrane thickening during the 5 years of study, and by the fifth year, excreted greater than normal quantities of albumin. Sorbinil treatment prevented sorbitol accumulation in erythrocytes and tended to have a similar effect in renal cortex, but had no beneficial effect on renal structure or albuminuria. Experimental galactosemia, another model of polyol over-production, failed to produce nephromegaly, glomerular enlargement, or mesangial expansion in dogs even after 5 years of galactose-feeding. The results suggest that polyol over-production and/or accumulation per se are not sufficient to account for the nephromegaly, glomerular enlargement, or increased mesangial volume observed in diabetic dogs.
Kern
T S
TS
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, USA.
Engerman
R L
RL
D000419:Albuminuria; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000704:Analysis of Variance; D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004912:Erythrocytes / Q000378:metabolism; D005690:Galactose / Q000633:toxicity; D005920:Glomerular Mesangium / Q000473:pathology; D006029:Glycosuria; D007093:Imidazoles / Q000627:therapeutic use*; D048289:Imidazolidines; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D007672:Kidney Cortex / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology; D013402:Sugar Alcohols / Q000378:metabolism; D013997:Time Factors
D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D013402:Sugar Alcohols; D000449:Aldehyde Reductase; C026411:sorbinil; D005690:Galactose