title: The effect of aldose reductase inhibitors on glomerular prostaglandin production and urinary albumin excretion in experimental diabetes mellitus.
abstract: The effect of two structurally unrelated aldose reductase inhibitors, sorbinil and ponalrestat, on glomerular prostaglandin production and urinary albumin excretion was investigated in rats with diabetes induced by streptozotocin. It was found that both aldose reductase inhibitors, when administered from the time of induction of the diabetes, significantly decreased the raised urinary albumin excretion in the diabetic rats, although it remained elevated compared with non-diabetic rats. Glomerular prostaglandin E and 6-keto-prostaglandin F1 alpha production was significantly increased in glomeruli obtained from the diabetic rats. Inhibition of aldose reductase caused a reduction in the raised glomerular prostaglandin production, although this remained above that observed in the non-diabetic rats. Subsequent experiments were performed to determine whether the effects of the aldose reductase inhibitors could be explained by effects on glomerular filtration rate. It was found that ponalrestat, at a dose which markedly reduced urinary albumin excretion, did not significantly affect glomerular filtration rate in non-diabetic rats, rats with untreated streptozotocin-induced diabetes and rats with diabetes partially treated with low dose insulin. Glomerular sorbitol concentrations were significantly elevated in untreated diabetic rats as early as two weeks after the induction of diabetes. It is concluded that the administration of aldose reductase inhibitors from the time of induction of diabetes significantly reduces glomerular prostaglandin production and urinary albumin excretion. The latter effect is not due to an effect on glomerular filtration rate. Increased polyol pathway activity may account in part for the increased glomerular prostaglandin production and urinary albumin excretion in early experimental diabetes.
authors.affiliation: University of Melbourne Department of Medicine, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: W P
authors.initials: WP
authors.lastname: Chang
authors.forename: E
authors.initials: E
authors.lastname: Dimitriadis
authors.forename: T
authors.initials: T
authors.lastname: Allen
authors.forename: M E
authors.initials: ME
authors.lastname: Dunlop
authors.forename: M
authors.initials: M
authors.lastname: Cooper
authors.forename: R G
authors.initials: RG
authors.lastname: Larkins
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis*; D000419:Albuminuria; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D048289:Imidazolidines; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010793:Phthalazines / Q000494:pharmacology* / Q000627:therapeutic use; D011458:Prostaglandins E / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007093:Imidazoles; D048289:Imidazolidines; D010793:Phthalazines; D011458:Prostaglandins E; C042829:ponalrestat; D015121:6-Ketoprostaglandin F1 alpha; D000449:Aldehyde Reductase; C026411:sorbinil