The effect of aldose reductase inhibitor Statil (ICI 128436) on the glucose over-utilization in kidney of diabetic rats.
The present study examined the effect of the aldose reductase inhibitor Statil (ICI 128436, ICI, Cheshire, U.K.) on the levels of metabolites and activities of enzymes involved in the glycolysis, polyol pathway and pentose phosphate pathway and on the flux of radioactive glucose through these pathways in kidney of streptozotocin diabetic rats. In kidneys of diabetic rats of 30 days duration the level of sorbitol was increased by +82% and fructose concentration was raised by +42%. After treatment with Statil for 9 days (reversal study) a significant fall in kidney sorbitol concentration and kidney fructose concentration was found. Lactate and UDP-glucose concentrations which were both significantly raised in diabetes by +80% and +23% respectively decreased by 20% after Statil treatment, together with a decline in UDP-glucose dehydrogenase activity. Aldose reductase and sorbitol dehydrogenase activities were also significantly lowered by Statil. In the reversal study there was no significant effect of Statil on the flux of glucose via alternative routes in the kidney cortex. In kidneys of diabetic rats of 9 days duration, the level of sorbitol increased by +61% and the concentration of fructose was raised by +30%. The treatment with Statil (25 mg/kg) from the day of induction of diabetes (prevention study) prevented the accumulation of sorbitol, fructose and UDP-glucose. The increase in the incorporation of radioactive glucose through the pentose phosphate pathway seen in diabetes was less marked in the renal cortex of diabetic rats treated with Statil ab initio.
Sochor
M
M
Department of Biochemistry, University College, London, U.K.
Kunjara
S
S
McLean
P
P
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D007668:Kidney / Q000033:anatomy & histology / Q000201:enzymology / Q000378:metabolism*; D007773:Lactates / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010428:Pentosephosphates / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D013012:Sorbitol / Q000378:metabolism; D014996:Xylulose / Q000378:metabolism
D005965:Glucuronates; D007773:Lactates; D010428:Pentosephosphates; D010793:Phthalazines; D011724:Pyridazines; C042829:ponalrestat; D013012:Sorbitol; D014996:Xylulose; D005947:Glucose