Renal and microvascular effects of an aldose reductase inhibitor in experimental diabetes. Biochemical, functional and ultrastructural studies.
Aldose reductase inhibitors, and particularly sorbinil, have been reported to prevent glomerular basement membrane thickening (GBMT) and albuminuria development in diabetic rats, but contradictory observations have been published. The aim of this study was to answer the following questions (i) is the corrective effect of sorbinil on GBMT, if confirmed, associated with an effect on collagen metabolism alterations? (ii) Is it associated with an effect on microvascular functional alterations? We therefore studied the influence of sorbinil on glucosyl-galactosyl-hydroxylysyl-glucohydrolase activity (GGHG; EC 3.2.1.107 which is involved in the catabolism of collagen disaccharide units), 3- and 4-hydroxyproline content and GBMT by ultrastructural morphometry in the kidney cortex of streptozotocin-diabetic rats after 5 months of disease. In parallel, the effects on albumin renal clearance and another functional alteration, the microvascular response to norepinephrine, were evaluated. We confirmed a corrective effect of sorbinil on both renal albumin clearance and GBMT. In the diabetic rats, sorbinil diminished the 3-hydroxyproline (but not the 4-hydroxyproline) content, whether expressed per mg protein or per total kidney cortex relative to body weight. Sorbinil reduced GGHG activity measured in the dialysed 10,000 g supernatant whether expressed per mg protein or per total kidney cortex; this activity has been shown to be increased in diabetes. Sorbinil also corrected the microvascular response to norepinephrine which is altered in diabetes.
Kassab
J P
JP
Equipe de Recherches sur la Biochimie et la Pharmacologie des Vaisseaux et du Rein, Faculté de Médecine, Paris, France.
Guillot
R
R
Andre
J
J
Claperon
N
N
Bellon
G
G
Feldmann
G
G
Peyroux
J
J
Sternberg
M
M
D000419:Albuminuria / Q000652:urine; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002196:Capillaries / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D006909:Hydroxyproline / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D048289:Imidazolidines; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000098:blood supply / Q000187:drug effects
D007093:Imidazoles; D048289:Imidazolidines; D003094:Collagen; D000449:Aldehyde Reductase; C026411:sorbinil; D006909:Hydroxyproline; D009638:Norepinephrine